Films and Particles

ABSTRACT

Described herein are compounds and processes that can be used to prepare polymer-based films, particles, gels and related compositions, and processes for delivery of agents, and other uses.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Provisional Application Ser.No. 60/809,334, filed on May 31, 2006, and U.S. Provisional ApplicationSer. No. 60/844,122, filed on Sep. 13, 2006, which are both incorporatedherein by reference in their entirety.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

This invention was made with Government support under U.S. ArmyCooperative agreement No. DAMD-17-02-2-0006. The Government has certainrights in the invention.

FIELD OF THE INVENTION

Provided herein are compounds and processes to prepare polymer basedfilms, particles, gels, and related compositions, and processes fordelivery of agents.

BACKGROUND OF THE INVENTION

Medicine traditionally utilizes pharmacologic agents or surgicalinterventions for the treatment of disease. Specific targeting orlocalization of pharmacologic or biological agents to desired organs andtissues is a complex challenge. For example, cancer is a leading causeof death for both men and women in the United States (Jemal et al., CACancer J. Clin., 56:106-130, 2006). Current methods of cancer treatmentinclude chemotherapy, radiation treatment, and surgical resection. Asevidenced by high rates of cancer recurrence and low survival,treatments of conditions such as cancer often remain relativelyineffective.

Other diseases and conditions which utilize drug delivery technologiesinclude immunological applications, pain control, wound healing,infectious disease, transplants, and the development of vaccines.Potential drug candidates often present solubility, toxicity, andpharmacokinetic considerations. Thus, there is a widespread need fortargeted and sustained delivery of therapeutic agents.

Certain polyesters, polycarbonates, and polyamides are biodegradablepolymers with low toxicity and degradation properties. Such polymersinclude poly(ε-caprolactone), poly(p-dioxanone), poly(trimethylenecarbonate), poly(amino acids), and most notably poly(glycolic acid) andpoly(lactic acid) (see, e.g., Agrawal et al., Biomaterials, 13:176-182,1992; Attawia et al., J. Biomed. Mater. Res., 29:1233-140, 1995; Helleret al., Adv. Drug Deliv. Rev., 54:1015-1039, 2002; Miller and Williams,Biomaterials, 8:129-137, 1987; and Athanasiou et al., Arthroscopy,14:726-737, 1998). These polymers are used in a variety of applicationsincluding the delivery of therapeutic agents. However, physicalproperties of the aforementioned polymers are often limited by monomerselection, polymerization techniques, and post-polymerizationmodifications. Properties of interest include thermal transitiontemperatures, bulk strength, flexibility, elasticity, degradation,crystallinity, and hydrophobicity. When polymers are utilized for invivo applications, the physical properties of the material affect hostresponse. Hence, a need exists for polymers and delivery systems withdesired characteristics that are effective for treatment of diseases andconditions.

SUMMARY OF THE INVENTION

The invention is based, at least in part, on the discovery that certainpolymer films and particles can be utilized therapeutically and/orcosmetically. For example, many of the films and particles describedherein can be used for the controlled, localized, and sustained deliveryof various agents for treatment of diseases and conditions. Providedherein are compounds and processes to prepare polymer based films,particles, gels, and related compositions, and processes for delivery ofagents. Provided herein are polymeric films and particles that deliverone or more agents, such as one or more therapeutic agents, to a localsite, where the release of the one or more agents from the film orparticle is initiated by a pH change. Also provided are biodegradablepolymers.

In one aspect, the invention features oligomers or polymers having arepeat unit represented by Formula XX:

In such oligomers or polymers, Q is selected from among O, S, Se, or NH;G is selected from among the following structures:

R₂ is selected from among hydrogen, a straight or branched alkyl,cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl,arylalkyl, or fluorocarbon chain of 1-50 carbons, wherein each alkyl,cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl,arylalkyl, or fluorocarbon chain is optionally substituted internally orterminally by one or more hydroxyl, hydroxyether, carboxyl,carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol,thioester, sulfate, phosphate, phosphonate, or halogen substituents; R₃is selected from among hydrogen, methoxy, ethoxy, amino, a straight orbranched alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl,alkylaryl, or arylalkyl chain of 1-10 carbons; R₄, R₅, and R₆ are eachindependently selected from among a straight or branched alkyl,cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, orarylalkyl chain of 1-10 carbons; and R₇ and R₈ are each independentlyselected from among hydrogen, a straight or branched alkyl, cycloalkyl,aryl, olefin, alkylaryl, or arylalkyl chain of 1-50 carbons, whereineach alkyl, cycloalkyl, aryl, olefin, alkylaryl, or arylalkyl chain isoptionally substituted internally or terminally by one or more hydroxyl,hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- ordi-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate,or halogen substituents.

In some embodiments, the oligomers or polymers are represented byFormula XX′:

In such embodiments, n is an integer from 2-750, and each oligomeric orpolymeric chain has a terminal group, the terminal group being selectedfrom among amines, thiols, amides, phosphates, sulphates, hydroxides,alkenes, and alkynes.

In another aspect, the invention features oligomers or polymers, orportions thereof, that are represented by Formula XXI, XXII, XXIII,XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV,XXXV, XXXVI or XXXVII:

In such oligomers or polymers, or portions thereof Q′ is independentlyselected from among O, S, Se, or NH; G′, G₁′, and G₂′ are eachindependently selected from among the following structures:

G₁′ and G₂′ are not the same; R₁′ is selected from among a straight orbranched alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl,alkylaryl, arylalkyl, or fluorocarbon chain of 3-50 carbons, whereineach alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl,alkylaryl, arylalkyl or fluorocarbon chain is optionally substitutedinternally or terminally by one or more hydroxyl, hydroxyether,carboxyl, carboxyester, carboxyamide, amino, mono- or di-substitutedamino, thiol, thioester, sulfate, phosphate, phosphonate, or halogensubstituents; or R₁′ is selected from among poly(ethylene glycol),poly(ethylene oxide), poly(hydroxyacid)), a carbohydrate, a protein, apolypeptide, an amino acid, a nucleic acid, a nucleotide, apolynucleotide, any DNA or RNA segment, a lipid, a polysaccharide, anantibody, a pharmaceutical agent, or any epitope for a biologicalreceptor; or R₁′ is selected from among a photocrosslinkable orionically crosslinkable group; R₂′ is selected from among hydrogen, astraight or branched alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl,arylsilyl, alkylaryl, arylalkyl, or fluorocarbon chain of 1-50 carbons.Each alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl,alkylaryl, arylalkyl, or fluorocarbon chain is optionally substitutedinternally or terminally by one or more hydroxyl, hydroxyether,carboxyl, carboxyester, carboxyamide, amino, mono- or di-substitutedamino, thiol, thioester, sulfate, phosphate, phosphonate, or halogensubstituents; x and y are each independently selected from an integer of2-750; a is selected from an integer of 1-25; b is selected from aninteger of 1-14; c is selected from an integer of 1-14; and eachpolymeric terminal group is selected from among amines, thiols, amides,phosphates, sulphates, hydroxides, metals, alkanes, alkenes and alkynes.

In another aspect, the invention features oligomers or polymers, orportions thereof, represented by Formula XXXVIII:

In such oligomers or polymers, or portions thereof, Q′ is independentlyselected from among O, S, Se, or NH;G′ is selected from among

or R₁′; R₁′ is selected from among a straight or branched alkyl,cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl,arylalkyl, or fluorocarbon chain of 3-50 carbons, wherein each alkyl,cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl,arylalkyl, or fluorocarbon chain is optionally substituted internally orterminally by one or more hydroxyl, hydroxyether, carboxyl,carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol,thioester, sulfate, phosphate, phosphonate, or halogen substituents; orR₁′ is selected from among poly(ethylene glycol), poly(ethylene oxide),poly(hydroxyacid)), a carbohydrate, a protein, a polypeptide, an aminoacid, a nucleic acid, a nucleotide, a polynucleotide, any DNA or RNAsegment, a lipid, a polysaccharide, an antibody, a pharmaceutical agent,or any epitope for a biological receptor; or R₁′ is selected from amonga photocrosslinkable or ionically crosslinkable group; x and y are eachindependently selected from an integer of 2-750; e is selected from aninteger of 1-8; and each polymeric terminal group is selected from amongamines, thiols, amides, phosphates, sulphates, hydroxides, metals,alkanes, alkenes and alkynes.

In another aspect, the invention features oligomers or polymers having arepeat unit represented by Formula XX:

In such oligomers or polymers G includes a first group that isconvertible to a second group different from the first group at a pH ator below about 6.0, such as below about 5.5, 5.0 or 4.5; R₂ is selectedfrom among hydrogen, a straight or branched alkyl, cycloalkyl, aryl,olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl, orfluorocarbon chain of 1-50 carbons. Each alkyl, cycloalkyl, aryl,olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl orfluorocarbon chain is optionally substituted internally or terminally byone or more hydroxyl, hydroxyether, carboxyl, carboxyester,carboxyamide, amino, mono- or di-substituted amino, thiol, thioester,sulfate, phosphate, phosphonate, or halogen substituents; and Q isselected from among O, S, Se, or NH.

In another aspect, the invention features particles having a firstvolume and including an oligomer or polymer having a repeat unitrepresented by Formula XX:

In such particles, G includes a first group that is convertible to asecond group different from the first group at a pH at or below about6.0, such as below about 5.5, 5.0, or 4.5; R₂ is selected from amonghydrogen, a straight or branched alkyl, cycloalkyl, aryl, olefin, silyl,alkylsilyl, arylsilyl, alkylaryl, arylalkyl, or fluorocarbon chain of1-50 carbons. Each alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl,arylsilyl, alkylaryl, arylalkyl, or fluorocarbon chain is optionallysubstituted internally or terminally by one or more hydroxyl,hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- ordi-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate,or halogen substituents; and Q is selected from among O, S, Se, or NH.When the particle is placed in an environment having a pH at or belowabout 6.0, the particle increases in volume from the first volume to asecond volume that is more than two times the first volume afterequilibrium is established.

Polymeric films or particles can include any oligomer or polymerdescribed herein. In some instances, the polymeric particles include afirst volume at a first pH, and a second volume at a second pH,different from the from the first pH. For example, the second volume is1× or more greater than the first volume when the second pH is lowerthan the first pH, such as 4× or more greater than the first volume whenthe second pH is lower than the first pH, or 8× or more greater than thefirst volume when the second pH is lower than the first pH.

Any film or particle can include a therapeutic agent. For example, theagent can be a biologically active agent comprising one or more of ananti-cancer agent, an anti-biotic, an anti-neoplastic agent, ananalgesic, an angiogenic, or an agent that promotes wound healing.

For example, the particles can be used for applying to one or more ofthe following: (i) a surgical resection margin, (ii) within a treated oruntreated tumor or cavity, (iii) a target site of disease away from asurgical margin, and (iv) a lymph node.

The particles or films can have one or more layers.

The particles can have a diameter or less than 500 nanometers, such asless than 250 nanometers or less than 100 nanometers. For example, theparticles can have a diameter of between about 1 nm and 2 microns.

Any of the particles described herein can be applied at a first site,such as a surgical margin, and then are carried by the body to a secondsite downstream of the first site, such as a lymph node. In such uses,it is desirable that the particles have a diameter of less than about250 nanometers, such as less than 100 nanometers, or even less than 50nanometers.

In another aspect, the invention features applying any film or particledescribed herein to a site using sutures, staples, and/or adhesives.

In another aspect, the invention features applying any film or particledescribed herein to treat pain, or to alter healing, e.g., to avoid scarformation.

Unless specific definitions are provided, e.g., as indicated below, thenomenclature used in connection with, and the laboratory procedures andtechniques of, analytical chemistry, biochemistry, synthetic organicchemistry, and medicinal and pharmaceutical chemistry described hereinare those known in the art. In the event that there is a plurality ofdefinitions for terms herein, those in this section prevail.

As used herein, the abbreviations for any protective groups, aminoacids, and other compounds are, unless indicated otherwise, in accordwith their common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature, Biochem., 11:942-944 (1972).

As used herein, use of the singular includes the plural unlessspecifically stated otherwise. As used herein, “or” means “and/or”unless stated otherwise. Furthermore, use of the term “including” aswell as other forms, such as “includes,” and “included,” is notlimiting.

As used herein, the terms “treating” or “treatment” encompass either orboth responsive and prophylaxis measures, e.g., designed to inhibit,slow or delay the onset of a symptom of a disease or disorder, achieve afull or partial reduction of a symptom or disease state, and/or toalleviate, ameliorate, lessen, or cure a disease or disorder and/or itssymptoms.

As used herein, amelioration of the symptoms of a particular disorder byadministration of a particular compound or pharmaceutical compositionrefers to any lessening of severity, delay in onset, slowing ofprogression, or shortening of duration, whether permanent or temporary,lasting or transient that can be attributed to or associated withadministration of the compound or composition.

As used herein, the term “subject” is a human or an animal, typically amammal, such as a cow, horse, dog, cat, pig, sheep, monkey, or otherlaboratory or domesticated animal. As used herein, the term “patient”includes human and animal subjects.

As used herein, the term “carrier” refers to a compound that facilitatesthe incorporation of another compound into cells or tissues. Forexample, dimethyl sulfoxide (DMSO) is a commonly used carrier forimproving incorporation of certain organic compounds into cells ortissues.

As used herein, the term “pharmaceutical composition” refers to achemical compound or composition capable of inducing a desiredtherapeutic effect in a subject. In certain embodiments, apharmaceutical composition contains an active agent, which is the agentthat induces the desired therapeutic effect. The pharmaceuticalcomposition can contain a prodrug of the compounds provided herein. Incertain embodiments, a pharmaceutical composition contains inactiveingredients, such as, for example, carriers and excipients.

As used herein, the term “therapeutically effective amount” refers to anamount of a pharmaceutical composition sufficient to achieve a desiredtherapeutic effect.

As used herein, the term “pharmaceutically acceptable” refers to aformulation of a compound that does not significantly abrogate thebiological activity, a pharmacological activity and/or other propertiesof the compound when the formulated compound is administered to asubject. In certain embodiments, a pharmaceutically acceptableformulation does not cause significant irritation to a subject.

As used herein, pharmaceutically acceptable derivatives of a compoundinclude, but are not limited to, salts, esters, enol ethers, enolesters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids,bases, solvates, hydrates, PEGylation, or prodrugs thereof. Suchderivatives can be readily prepared by those of skill in this art usingknown methods for such derivatization. The compounds produced can beadministered to animals or humans without substantial toxic effects andeither are pharmaceutically active or are prodrugs. Pharmaceuticallyacceptable salts include, but are not limited to, amine salts, such asbut not limited to chloroprocaine, choline,N,N′-dibenzyl-ethylenediamine, ammonia, diethanolamine and otherhydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine,N-benzyl-phenethylamine,1-para-chloro-benzyl-2-pyrrolidin-1′-ylmethyl-benzimidazole,diethylamine and other alkylamines, piperazine andtris(hydroxymethyl)-aminomethane; alkali metal salts, such as but notlimited to lithium, potassium and sodium; alkali earth metal salts, suchas but not limited to barium, calcium and magnesium; transition metalsalts, such as but not limited to zinc; and other metal salts, such asbut not limited to sodium hydrogen phosphate and disodium phosphate; andalso including, but not limited to, salts of mineral acids, such as butnot limited to hydrochlorides and sulfates; and salts of organic acids,such as but not limited to acetates, lactates, malates, tartrates,citrates, ascorbates, succinates, butyrates, valerates and fumarates.Pharmaceutically acceptable esters include, but are not limited to,alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl,cycloalkyl and heterocyclyl esters of acidic groups, including, but notlimited to, carboxylic acids, phosphoric acids, phosphinic acids,sulfonic acids, sulfinic acids and boronic acids. Pharmaceuticallyacceptable enol ethers include, but are not limited to, derivatives offormula C═C(OR) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, or heterocyclyl.Pharmaceutically acceptable enol esters include, but are not limited to,derivatives of formula C═C(OC(O)R) where R is hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, orheterocyclyl. Pharmaceutically acceptable solvates and hydrates arecomplexes of a compound with one or more solvent or water molecules, or1 to about 100, or 1 to about 10, or one to about 2, 3, or 4, solvent orwater molecules.

“Alkyl” refers to an aliphatic hydrocarbon group which can be straightor branched having 1 to about 60 carbon atoms in the chain, and whichpreferably have about 6 to about 50 carbons in the chain. “Lower alkyl”refers to an alkyl group having 1 to about 8 carbon atoms. “Higheralkyl” refers to an alkyl group having about 10 to about 20 carbonatoms. The alkyl group can be optionally substituted with one or morealkyl group substituents which can be the same or different, where“alkyl group substituent” includes halo, amino, aryl, hydroxy, alkoxy,aryloxy, alkyloxy, alkylthio, arylthio, aralkyloxy, aralkylthio,carboxy, alkoxycarbonyl, oxo and cycloalkyl. There can be optionallyinserted along the alkyl chain one or more oxygen, silicon, sulfur, orsubstituted or unsubstituted nitrogen atoms, wherein the nitrogensubstituent is lower alkyl. “Branched” refers to an alkyl group in whicha lower alkyl group, such as methyl, ethyl, or propyl, is attached to alinear alkyl chain. Exemplary alkyl groups include methyl, ethyl,i-propyl, n-butyl, t-butyl, n-pentyl, heptyl, octyl, decyl, dodecyl,tridecyl, tetradecyl, pentadecyl and hexadecyl. Useful alkyl groupsinclude branched or straight chain alkyl groups of 6 to 50 carbon, andalso include the lower alkyl groups of 1 to about 4 carbons and thehigher alkyl groups of about 12 to about 16 carbons.

“Alkenyl” refers to an alkyl group containing at least one carbon-carbondouble bond. The alkenyl group can be optionally substituted with one ormore “alkyl group substituents.” Exemplary alkenyl groups include vinyl,allyl, n-pentenyl, decenyl, dodecenyl, tetradecadienyl,heptadec-8-en-1-yl and heptadec-8,1,1-dien-1-yl.

“Alkynyl” refers to an alkyl group containing a carbon-carbon triplebond. The alkynyl group can be optionally substituted with one or more“alkyl group substituents.” Exemplary alkynyl groups include ethynyl,propargyl, n-pentynyl, decynyl, and dodecynyl. Useful alkynyl groupsinclude the lower alkynyl groups.

“Cycloalkyl” refers to a non-aromatic mono- or multicyclic ring systemof about 4 to about 10 carbon atoms. The cycloalkyl group can beoptionally partially unsaturated. The cycloalkyl group can be alsooptionally substituted with an aryl group substituent, oxo and/oralkylene. Representative monocyclic cycloalkyl rings includecyclopentyl, cyclohexyl, and cycloheptyl. Useful multicyclic cycloalkylrings include adamantyl, octahydronaphthyl, decalin, camphor, camphane,and noradamantyl.

“Aryl” refers to an aromatic carbocyclic radical containing about 6 toabout 10 carbon atoms. The aryl group can be optionally substituted withone or more aryl group substituents, which can be the same or different,where “aryl group substituent” includes alkyl, alkenyl, alkynyl, aryl,aralkyl, hydroxy, alkoxy, aryloxy, aralkoxy, carboxy, aroyl, halo,nitro, trihalomethyl, cyano, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, acyloxy, acylamino, aroylamino, carbamoyl,alkylcarbamoyl, dialkylcarbamoyl, rylthio, alkylthio, alkylene, and—NRR′, where R and R′ are each independently hydrogen, alkyl, aryl, andaralkyl. Exemplary aryl groups include substituted or unsubstitutedphenyl and substituted or unsubstituted naphthyl.

“Acyl” refers to an alkyl-CO— group, wherein alkyl is as previouslydescribed. Exemplary acyl groups comprise alkyl of 1 to about 30 carbonatoms. Exemplary acyl groups also include acetyl, propanoyl,2-methylpropanoyl, butanoyl, and palmitoyl.

“Aroyl” means an aryl-CO— group, wherein aryl is as previouslydescribed. Exemplary aroyl groups include benzoyl, and 1- and2-naphthoyl.

“Alkoxy” refers to an alkyl-O— group, wherein alkyl is as previouslydescribed. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, and heptoxy.

“Aryloxy” refers to an aryl-O— group, wherein the aryl group is aspreviously described. Exemplary aryloxy groups include phenoxy andnaphthoxy.

“Alkylthio” refers to an alkyl-S— group, wherein alkyl is as previouslydescribed. Exemplary alkylthio groups include methylthio, ethylthio,i-propylthio, and heptylthio.

“Arylthio” refers to an aryl-S— group, wherein the aryl group is aspreviously described. Exemplary arylthio groups include phenylthio andnaphthylthio.

“Aralkyl” refers to an aryl-alkyl— group, wherein aryl and alkyl are aspreviously described. Exemplary aralkyl groups include benzyl,phenylethyl, and naphthylmethyl.

“Aralkyloxy” refers to an aralkyl-O— group, wherein the aralkyl group isas previously described. An exemplary aralkyloxy group is benzyloxy.

“Aralkylthio” refers to an aralkyl-S— group, wherein the aralkyl groupis as previously described. An exemplary aralkylthio group isbenzylthio.

“Dialkylamino” refers to an— NRR′ group, wherein each of R and R′ isindependently an alkyl group as previously described. Exemplaryalkylamino groups include ethylmethylamino, dimethylamino, anddiethylamino.

“Alkoxycarbonyl” refers to an alkyl-O—CO— group. Exemplaryalkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl,butyloxycarbonyl, and t-butyloxycarbonyl.

“Aryloxycarbonyl” refers to an aryl-O—CO— group. Exemplaryaryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl.

“Aralkoxycarbonyl” refers to an aralkyl-O—CO— group. An exemplaryaralkoxycarbonyl group is benzyloxycarbonyl.

“Carbamoyl” refers to an H₂N—CO— group.

“Alkylcarbamoyl” refers to a R′RN—CO— group, wherein one of R and R′ ishydrogen and the other of R and R′ is alkyl as previously described.

“Dialkylcarbamoyl” refers to R′RN—CO— group, wherein each of R and R′ isindependently alkyl as previously described.

“Acyloxy” refers to an acyl-O— group, wherein acyl is as previouslydescribed.

“Acylamino” refers to an acyl-NH— group, wherein acyl is as previouslydescribed.

“Aroylamino” refers to an aroyl-NH— group, wherein aroyl is aspreviously described.

“Alkylene” refers to a straight or branched bivalent aliphatichydrocarbon group having from 1 to about 30 carbon atoms. The alkylenegroup can be straight, branched, or cyclic. The alkylene group can bealso optionally unsaturated and/or substituted with one or more “alkylgroup substituents.” There can be optionally inserted along the alkylenegroup one or more oxygen, sulphur, or substituted or unsubstitutednitrogen atoms, wherein the nitrogen substituent is alkyl as previouslydescribed. Exemplary alkylene groups include methylene (—CH₂—), ethylene(—CH₂—CH₂—), propylene (—(CH₂)₃—), cyclohexylene (—C₆H₁₀—),—CH═CH—CH═CH—, —CH═CH—CH₂—, —(CF₂)_(n)(CH₂)_(m)—, wherein n is aninteger from about 1 to about 50 and m is an integer from 0 to about 50,—(CH₂)_(n)—N(R)—(CH₂)_(m)—, wherein each of m and n is independently aninteger from 0 to about 50 and R is hydrogen or alkyl, methylenedioxy(—O—CH₂—O—), and ethylenedioxy (—O—(CH₂)₂—O—). An alkylene group canhave about 2 to about 3 carbon atoms and can further have 6-50 carbons.

“Halo” or “halide” refers to fluoride, chloride, bromide, or iodide.

The term “agent” includes without limitation, medicaments, vitamins,mineral supplements, substances used for the treatment, prevention,diagnosis, cure or mitigation of disease or illness, substances thataffect the structure or function of the body, or pro-drugs, which becomebiologically active or more active after they have been placed in apredetermined physiological environment.

A “bioactive agent” refers to an agent that is capable of exerting abiological effect in vitro and/or in vivo. The biological effect can betherapeutic in nature. As used herein, “bioactive agent” refers also toa substance that is used in connection with an application that isdiagnostic in nature, such as in methods for diagnosing the presence orabsence of a disease in a patient. The bioactive agents can be neutralor positively or negatively charged. Examples of suitable bioactiveagents include pharmaceuticals and drugs, cells, gases and gaseousprecursors (e.g., O₂), synthetic organic molecules, proteins, enzymes,growth factors, vitamins, steroids, polyanions, nucleosides,nucleotides, polynucleotides, and diagnostic agents, such as contrastagents for use in connection with magnetic resonance imaging,ultrasound, positron emission transmography, computed tomography, orother imaging modality of a patient.

“Genetic material” refers generally to nucleotides and polynucleotides,including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Thegenetic material can be made by synthetic chemical methodology known toone of ordinary skill in the art, or by the use of recombinanttechnology, or by a combination of the two. The DNA and RNA canoptionally comprise unnatural nucleotides and can be single or doublestranded. “Genetic material” refers also to sense and anti-sense DNA andRNA, that is, a nucleotide sequence that is complementary to a specificsequence of nucleotides in DNA and/or RNA.

The polymers provided herein can be utilized therapeutically and/orcosmetically. For example, the polymers in any form described herein canbe used to promote healing and/or that inhibit disease by targeting drugdelivery to local and regional areas. The polymers provided herein canalso be used for a variety of applications including, but not limitedto, production of micro- and nanoparticles, films, coatings, sutures,and orthopedic materials. Such materials can be used to repair aninjured tissue, organ, bone, or genetic defect. Other uses of thepolymers provided herein include treatment of early, late, or previouslytreated malignancies, pretreatment of malignancies or other condition asa sensitizer to augment therapy of another agent such as with radiationsensitizers, avoidance of locoregional lymph node metastasis,augmentation of local wound healing and decrease in infection,manipulation of structure and abnormal scar formation, and for thetreatment of post-operative pain. In certain embodiments, the polymersprovided herein are used to treat cancer. For example, the polymersprovided herein can be used to treat various malignancies, e.g., lung,colon, prostate, pancreas, or breast cancer. For example, when a filmcarrying one or more therapeutic agents is utilized to treat a cancer,it can be stapled, sutured and/or glued in place, e.g., with acyanoacrylate resin.

The polymers provided herein can also be used to deliver any agent. Theagent can be in any pharmaceutically acceptable form, includingpharmaceutically acceptable salts. A large number of pharmaceuticalagents are known in the art and are amenable for use in thepharmaceutical compositions of the polymeric materials described herein.Acceptable agents include, but are not limited to, chemotherapeuticagents, such as radiosensitizers, receptor inhibitors and agonists orother anti-neoplastic agents; immune modulators and bioactive agents,such as cytokines, growth factors, or steroids with or without theco-incorporation of tumor or pathogen antigens to increase theanti-neoplastic response as a means of vaccine development; localanesthetic agents; antibiotics; or nucleic acids as a means of localgene therapy.

Unless otherwise defined, e.g., as above, all technical and scientificterms used herein have the same meaning as commonly understood by one ofordinary skill in the art to which this invention belongs. Althoughmethods and materials similar or equivalent to those described hereincan be used in the practice or testing of the present invention,suitable methods and materials are described below. All publications,patent applications, patents, and other references mentioned herein areincorporated by reference in their entirety, unless noted otherwise. Incase of conflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and not intended to be limiting.

Where reference is made to a URL or other such identifier or address, itunderstood that such identifiers can change and particular informationon the internet can come and go, but equivalent information can be foundby searching the internet Reference thereto evidences the availabilityand public dissemination of such information.

Standard techniques can be used for chemical syntheses, chemicalanalyses, pharmaceutical preparation, formulation and delivery, andtreatment of subjects. Standard techniques can be used for recombinantDNA, oligonucleotide synthesis, and tissue culture and transformation(e.g., electroporation, lipofection). Reactions and purificationtechniques can be performed, e.g., using kits according tomanufacturer's specifications or as commonly accomplished in the art oras described herein. The foregoing techniques and procedures generallyare performed according to conventional methods well known in the artand as described in various general and more specific references thatare cited and discussed throughout the present specification. See e.g.,Sambrook et al., Molecular Cloning: A Laboratory Manual (2d ed., ColdSpring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989).

Other features and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

BRIEF FIGURE DESCRIPTION

FIG. 1 is a bar graph showing the number of cells after treatment with10-hydroxycamptothecin loaded films, control films without10-hydroxycamptothecin, blank films, and 10-hydroxycamptothecin alone.

FIG. 2 is a bar graph showing the number of cells after treatment with10-hydroxycamptothecin loaded films, control films without10-hydroxycamptothecin, blank films, and 10-hydroxycamptothecin alone.

FIG. 3 is a bar graph showing the cytotoxicity ofpoly(glycerol-co-caprolactone) nanoparticles.

FIG. 4 is a bar graph showing the cytotoxicity ofpoly(glycerol-co-caprolactone) nanoparticles with 10% paclitaxel.

FIG. 5 is a bar graph showing the cytotoxicity ofpoly(glycerol-co-caprolactone) nanoparticles with 1% paclitaxel.

FIG. 6 is a graph showing the release of 10-hydroxycamptothecin frompoly(lauric, myristic, palmitic, or stearic glycerolcarbonate-co-caprolactone) films.

FIG. 7 is a graph showing 10-hydroxycamptothecin release frompoly(stearic glycerol carbonate-co-caprolactone) films on pericardiumstrips.

FIGS. 8A and 8B are scanning electron micrographs of10-hydroxycamptothecin-loaded poly(stearic glycerolcarbonate-co-ε-caprolactone) films; FIG. 8A shows the surface of thefilm (scale bar=3 microns), and FIG. 8B shows the film in cross-section(scale bar=10 microns).

FIG. 9 is a graph showing particle swelling at various pHs.

FIG. 10 is a graph showing the deprotection observed by absorbance usingUV/V is spectroscopy at a wavelength of 292 nm.

FIG. 11 is a scanning electron microscope (SEM) image of nanoparticles.

FIG. 12 is a graph of the diameter of sugar derived nanospheres atvarious pHs.

FIG. 13 is a bar graph showing tumor volume in response tochemotherapy-loaded nanoparticles.

FIG. 14 is a bar graph showing tumor volume in response to subcutaneouspolymer film implantation.

FIG. 15 is a bar graph showing the percentage of tumor growth inresponse to loaded 10-HCPT and unloaded films.

FIG. 16 is a bar graph showing the anti-cancer activity of paclitaxelloaded nanoparticles with LLC (lung cancer) cells in vitro.

FIG. 17 is a bar graph showing the activity of paclitaxel loadednanoparticles with mesothelioma cells in vitro.

FIG. 18 is a bar graph showing the anti-cancer activity of paclitaxelloaded nanoparticles with A459 human lung cancer cells in vitro.

DETAILED DESCRIPTION

Provided herein are compounds and processes to prepare polymer basedfilms, particles, gels, and related compositions, and processes fordelivering agents. The following describes the synthesis of monomerunits and the polymerization of those monomer units. Also provided isthe synthesis of polymeric structures that incorporate therapeuticagents and methods of using such compositions to treat various diseasesand disorders.

We will first describe vinyl monomers that can be used in making the newpolymers, as well as methods of synthesizing the monomers. We will thendescribe methods of preparing and using the polymers. Then, we willdescribe the preparation of films and particles, as well as theincorporation of agents into polymeric structures. Finally, we willdiscuss the applications of the polymers and polymer-agent combinations.

A. Vinyl Monomer Units

As shown below, various vinyl monomer units are disclosed herein. Thesemonomer units are used to prepare polymers, as described in furtherdetail below. Vinyl monomer units include compounds of Formula I, II,and III:

where each Q is independently selected from among O, S, Se, or NH;

G, or G and Q together, are selected from among:

R₁ is selected from among a straight or branched alkyl, cycloalkyl,aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl, orfluorocarbon chain of 3-50 carbons, wherein each alkyl, cycloalkyl,aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl, orfluorocarbon chain is optionally substituted internally or terminally byone or more hydroxyl, hydroxyether, carboxyl, carboxyester,carboxyamide, amino, mono- or di-substituted amino, thiol, thioester,sulfate, phosphate, phosphonate, or halogen substituents; or

R₁ is selected from among poly(ethylene glycol), poly(ethylene oxide),poly(hydroxyacid)), a carbohydrate, a protein, a polypeptide, an aminoacid, a nucleic acid, a nucleotide, a polynucleotide, any geneticmaterial, such as a DNA or RNA segment, a lipid, a polysaccharide, anantibody, a pharmaceutical agent, or any epitope for a biologicalreceptor; or

R₁ is selected from among a photocrosslinkable or ionicallycrosslinkable group; or

R₁ comprises a first group that is convertible to a second groupdifferent from the first group at a pH at or below about 6.0;

R₂ is selected from among hydrogen, a straight or branched alkyl,cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl,arylalkyl or fluorocarbon chain of 1-50 carbons, wherein the alkyl,cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl,arylalkyl or fluorocarbon chain is optionally substituted internally orterminally by one or more hydroxyl, hydroxyether, carboxyl,carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol,thioester, sulfate, phosphate, phosphonate, or halogen substituents; and

R″₂ is selected from among a straight or branched alkyl, cycloalkyl,aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl, orfluorocarbon chain of 1-50 carbons, wherein the alkyl, cycloalkyl, aryl,olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl, orfluorocarbon chain is optionally substituted internally or terminally byone or more hydroxyl, hydroxyether, carboxyl, carboxyester,carboxyamide, amino, mono- or di-substituted amino, thiol, thioester,sulfate, phosphate, phosphonate, or halogen substituents.

In certain embodiments, a compound of Formula II is selected from amonga compound shown below:

where R″₂ and G are independently selected as defined herein.

In certain embodiments, the compound of Formula II is a compound ofFormula IV, where Q is oxygen. In certain embodiments, the compound ofFormula II is a compound of Formula V, where Q is sulfur. In certainembodiments, the compound of Formula II is a compound of Formula VI,where Q is Se. In certain embodiments, the compound of Formula II is acompound of Formula VII, where Q is NH.

In other embodiments, a compound of Formula III is selected from among acompound Formula VIII, IX, X, or XI, as shown above. In certainembodiments, the compound of Formula III is a compound of Formula VIIIwhere Q is oxygen. In certain embodiments, the compound of Formula IIIis a compound of Formula IX, where Q is sulfur. In certain embodiments,the compound of Formula III is a compound of Formula X, where Q is Se.In certain embodiments, the compound of Formula III is a compound ofFormula XI, where Q is NH.

In other embodiments, a compound of Formula II is selected from among acompound Formula XII, XIII, or XIV, as shown below:

where R″₂ and G are independently selected as defined herein.

In certain embodiments, the compound of Formula II is a compound ofFormula XII. In certain embodiments, the compound of Formula II is acompound of Formula XIII. In certain embodiments, the compound ofFormula II is a compound of Formula XIV.

A compound of Formula III can also be independently selected from amonga compound of Formula XV, XVI, or XVII, as shown above.

In certain embodiments, each G group is selected from among a groupshown below:

where each Q is independently selected from among O, S, Se, or NH;

R₃ is selected from among hydrogen, methoxy, ethoxy, amino, a straightor branched alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl,arylsilyl, alkylaryl, or arylalkyl chain of 1-10 carbons;

R₄ and R₅ are each independently selected from among a straight orbranched alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl,alkylaryl, or arylalkyl chain of 1-10 carbons; and

R₇ is selected from among hydrogen, a straight or branched alkyl,cycloalkyl, aryl, olefin, alkylaryl, or arylalkyl chain of 1-50 carbons,wherein the alkyl, cycloalkyl, aryl, olefin, alkylaryl, or arylalkylchain is optionally substituted internally or terminally by one or morehydroxyl, hydroxyether, carboxyl, carboxyester, carboxyamide, amino,mono- or di-substituted amino, thiol, thioester, sulfate, phosphate,phosphonate, or halogen substituents.

In certain embodiments, each G group is selected from among a groupshown below:

where each Q, R₄, and R₅ are each independently selected as definedherein.

In certain embodiments, each G group is selected from among a groupshown below:

where each Q, R₂, R₃, R₄, R₅, and R₇ are selected as defined herein;

R₆ is selected from among a straight or branched alkyl, cycloalkyl,aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, or arylalkylchain of 1-10 carbons; and

R₈ is selected from among hydrogen, a straight or branched alkyl,cycloalkyl, aryl, olefin, alkylaryl, or arylalkyl chain of 1-50 carbons,wherein the alkyl, cycloalkyl, aryl, olefin, alkylaryl, or arylalkylchain is optionally substituted internally or terminally by one or morehydroxyl, hydroxyether, carboxyl, carboxyester, carboxyamide, amino,mono- or di-substituted amino, thiol, thioester, sulfate, phosphate,phosphonate, or halogen substituents.

In certain embodiments, each G group is selected from among a groupshown below:

where each Q, R₂, R₄, and R₅ are independently selected as definedherein.

In certain embodiments, R₂ of Formula I is selected from among hydrogen,C₁-C₂₀ alkyl, cycloalkyl, alkylcycloalkyl, aryl, and heteroaryl. Incertain embodiments, R₂ of Formula I is selected from among C₁-C₂₀alkyl, cycloalkyl, aryl, and heteroaryl. In certain embodiments, the R₂of Formula I is selected from among any group shown below:

In certain embodiments, R₂ of Formula I is selected from among, C₁-C₂₀alkyl, C₁-C₂₀ haloalkyl, heteroalkyl, cycloalkyl, alkylcycloalkyl, aryl,and heteroaryl, wherein the alkyl, haloalkyl, heteroalkyl, cycloalkyl,alkylcycloalkyl, aryl, and heteroaryl are optionally substituted. Incertain embodiments, R₂ of Formula I is selected from among C₁-C₂₀alkyl, wherein the alkyl is optionally substituted with halo, OH, NH₂,NH(CH₃), N(CH₃)₂, or COOH. In certain embodiments, the R₂ of Formula Iis selected from among any group shown below:

B. Methods of Synthesizing Vinyl Monomer Units

As shown below, the vinyl monomer units described herein can, e.g., besynthesized by reacting a compound of Formula I′ to provide a compoundof Formula I:

where each Q, G, or Q and G together, and R₂ are independently selectedas defined herein;

and LG is a leaving group such as Cl or Br.

In one embodiment, a compound of Formula HQG, where Q and G are asdefined herein, is dissolved in a solvent such as hexane, benzene,toluene, diethyl ether, chloroform, ethyl acetate, dichloromethane,1,4-dioxane, tetrahydrofuran (THF), acetone, acetonitrile (MeCN),dimethylformamide (DMF), dimethyl sulfoxide, acetic acid, n-butanol,isopropanol, n-propanol, ethanol, methanol or water. In certainembodiments, a compound of Formula HQG is dissolved in THF. To thissolution is added an acryloyl halide, such as methacryloyl chloride. Incertain embodiments a base, such as a trialkyl amine (e.g.triethylamine), is added to the reaction mixture. The resulting productis a compound of Formula I.

In another embodiment, a compound of Formula I is prepared by reacting acompound of Formula HQG, where Q and G are defined as above, with anacryl anhydride, such as methacrylic anhydride, in the presence of abase, such as triethyl amine.

C. Methods of Polymerizing Vinyl Monomer Units

As shown below, a compound of Formula I can be polymerized to yield acompound of Formula XX:

where each Q, G, or G and Q together, and R₂ are independently selectedas defined herein;

and n is an integer from 2-750; and

each polymeric terminal group is selected from among amines, thiols,amides, phosphates, sulphates, hydroxides, alkenes, and alkynes.

Any method of vinyl polymerization known in the art can be used for thisreaction. For example, a compound of Formula I can be reacted with afree-radical initiator. Free-radical initiators include halogenmolecules, such as Cl₂, azo compounds, such as2,2′-azobis(2-methylpropionitrile) (AIBN), and organic peroxides, suchas di-t-butylperoxide. The polymerization can also be induced by lightand a photoinitiator.

In one embodiment, a compound of Formula I is dissolved in a solvent,such as hexane, benzene, toluene, diethyl ether, chloroform, ethylacetate, dichloromethane, 1,4-dioxane, tetrahydrofuran (THF), acetone,acetonitrile (MeCN), dimethylformamide (DMF), or dimethyl sulfoxide, andreacted with AIBN to yield a compound of Formula XX.

In certain embodiments, the polymer of Formula XX is hydrophobic andcontains a pH sensitive group. G groups that are pH sensitive can beselected from among the groups described herein. As shown above,polymers of Formula XXI can be obtained by acid catalyzed hydrolysisfrom polymers of Formula XX, which contain a pH sensitive group. Anymethod of acid catalyzed hydrolysis known in the art can be used forthis transformation. For example, the hydrolysis can be realized byimmersing the polymer of Formula XX into a hydrochloric acid solution.The pH of the solution can be between 0.1 and 6.5. In other embodiments,the pH of the solution is between 1 and 5. For example, the pH can bebelow about 6.0, 5.5, 5.0, 4.5 or 4.0. In certain embodiments, the pHaround 4. In other embodiments, the pH sensitive group can be removedunder basic conditions and/or can be cleaved enzymatically.

As shown above, the hydrophilic polymer of Formula XXI can increase insize as compared to the hydrophobic polymer of Formula XX. The increasedsize (S₂) can be between 1.5 and 20 or more times the original size(S₁). In certain embodiments, the change in size from S₁ to S₂ isbetween 2 and 20 times, e.g., between 5 and 15, 5 and 10, 2 and 4, or 8and 10 times, the original size.

E. Additional Vinyl Monomers, Polymerizations, and Hydrolysis Conditions

As shown below, a compound, e.g., compound 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, or 16, is polymerized alone or in combinationwith another monomer, to form a polymer, e.g., compound 1a, 2a, 3a, 4a,5a, 6a, 7a, 8a, 9a, 10a, 11a, 12a, 13a, 14a, 15a, or 16a. Any method ofpolymerization described herein can be used for this transformation. Forexample, compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or16 can be reacted with a free-radical initiator, such as2,2′-azobis(2-methylpropionitrile) (AIBN). The resulting compound 1a,2a, 3a, 4a, 5a, 6a, 7a, 8a, 9a, 10a, 11a, 12a, 13a, 14a, 15a, or 16a isgenerally a hydrophobic polymer with a pH sensitive group. Any method ofacid catalyzed hydrolysis known in the art can be used to cleave the pHsensitive group, as described herein. Enzymatic hydrolysis alone, or incombination with an acidic or basic solution, can also be used to cleavethe group. For example, compound 1a, 2a, 3a, 4a, 5a, 6a, 7a, 8a, 9a,10a, 11a, 12a, 13a, 14a, 15a, or 16a can be immersed in a hydrochloricacid solution. The resulting compound 1b, 2b, 3b, 4b, 5b, 6b, 9b, 10b,11b, 12b, 13b, 14b, 15b, or 16b is a hydrophilic polymer and canincrease in size between 1.5 and 20 or more times the original size ofcompound 1a, 2a, 3a, 4a, 5a, 6a, 7a, 8a, 9a, 10a, 11a, 12a, 13a, 14a,15a, or 16a, respectively. For example, compound 1a, 2a, 3a, 4a, 5a, 6a,7a, 8a, 9a, 10a, 11a, 12a, 13a, 14a, 15a, or 16a can be exposed to anacidic solution for various periods of time. Longer periods of exposurecan lead to greater swelling. Alternative methods of achieving greatergrowth include raising the temperature and lowering the pH. The degreeto which the particle swells can be reduced by adding difunctionalcrosslinkers. Difunctional crosslinkers include di-acrylate species andprovide crosslinking between ploymer chains that further restrict thesize of the particle upon expansion.

Compounds 1, 2, 3, and 4 individually are polymerized to form a polymer,e.g., compound 1a, 2a, 3a, and 4a, as shown below:

where each Q, n, R₂, R₃, R₇, and terminal group are independentlyselected as defined herein.

Compounds 5 and 6 are individually polymerized to form a polymer, e.g.compound 5a and 6a, as shown below:

where each Q, n, R₂, R₄, R₅, and terminal group are independentlyselected as defined herein.

Compound 7 and 8 are individually polymerized to form a polymer, e.g.compound 7a and 8a, as shown below:

where each Q, n, R₂, R₄, R₅, and terminal group are independentlyselected as defined herein.

Compounds 9 and 10 are individually polymerized to form a polymer, e.g.,compound 9a and 10a, as shown below:

where each Q, n, R₂, R₄, R₅, and terminal group are independentlyselected as defined herein.

Compounds 11 and 12 are individually polymerized to form a polymer,e.g., compound 11a and 12a, as shown below:

where each Q, n, R₂, R₄, R₅, R₆, and terminal group are independentlyselected as defined herein.

Compounds 13 and 14 are individually polymerized to form a polymer,e.g., compound 13a and 14a, as shown below:

where each Q, n, R₂, R₄, R₅, and terminal group are independentlyselected as defined herein.

Compounds 15 and 16 are individually polymerized to form a polymer, e.g.compound 15a and 16a, as shown below:

where each Q, n, R₂, R₃, R₄, R₅, R₇, R₈, and terminal group areindependently selected as defined herein.F. Vinyl Homopolymers and Copolymers

Provided herein are homopolymers prepared by polymerizing a compound ofFormula I. In some embodiments, compounds of Formula I can beco-polymerized with any vinyl monomer described herein or known in theart. For example, Compound 1 can be co-polymerized with Compound 2.Compound 3 can be co-polymerized with any vinyl monomer known in theart, for example methyl methacrylate.

In other embodiments, any compounds of Formula I can be co-polymerizedwith any vinyl monomer described herein or known in the art to produce arandom copolymer, a block copolymer, alternating copolymer, or a graftcopolymer using any methods known in the art.

In additional embodiments, any compound of Formula I can beco-polymerized with any vinyl monomer described herein or known in theart to yield a linear, branched, star, or comb polymer, again, using anymethods known in the art.

Any ratio of a single monomer relative to another monomer can be used toform a copolymer. Different ratios of monomer units impart differentphysical and chemical properties to the copolymer. Properties ofinterest include, but are not limited to, thermal transitiontemperature, bulk strength, crystallinity, flexibility, elasticity, andhydrophobicity. Thus, by varying monomer ratios, it is possible toafford a copolymer with desired characteristics. For example,introduction of a bulky hydrophobic side group will make the polymermore hydrophobic and reduce the rate of hydrolysis.

G. Additional Polymers such as Polyesters, Polyethers, andPolycarbonates

The following polyesters, polyethers, polyether-esters, polyamides,polycarbonates, and polyamino acids can be prepared according to thedescription provided below. These polymers can be used to make thefilms, particles, gels, and related compositions described herein, andcan be used, e.g., to deliver various agents, e.g., bioactive agents.

As shown below, the chemical structures of various new polymers havingFormulas XXI, XXII, XXIII, and XXIV:

where each Q′ is independently selected from among O, S, Se, or NH;

G′, G₁′, and G₂′ are each independently selected from among:

or R₁′; wherein G₁′ and G₂′ are not the same;

R₁′ is selected from among a straight or branched alkyl, cycloalkyl,aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl orfluorocarbon chain of 3-50 carbons, wherein the alkyl, cycloalkyl, aryl,olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl orfluorocarbon chain is optionally substituted internally or terminally byone or more hydroxyl, hydroxyether, carboxyl, carboxyester,carboxyamide, amino, mono- or di-substituted amino, thiol, thioester,sulfate, phosphate, phosphonate, or halogen substituents; or

R₁′ is selected from among poly(ethylene glycol), poly(ethylene oxide),poly(hydroxyacid)), a carbohydrate, a protein, a polypeptide, an aminoacid, a nucleic acid, a nucleotide, a polynucleotide, any DNA or RNAsegment, a lipid, a polysaccharide, an antibody, a pharmaceutical agent,or any epitope for a biological receptor; or

R₁′ is selected from among a photocrosslinkable or ionicallycrosslinkable group; or

R₁′ comprises a first group that is convertible to a second groupdifferent from the first group at a pH at or below about 6.0;

R₂′ is selected from among hydrogen, a straight or branched alkyl,cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl,arylalkyl, or fluorocarbon chain of 1-50 carbons, wherein the alkyl,cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl,arylalkyl, or fluorocarbon chain is optionally substituted internally orterminally by one or more hydroxyl, hydroxyether, carboxyl,carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol,thioester, sulfate, phosphate, phosphonate, or halogen substituents;

x and y are each independently selected from an integer of 1-750; and

each polymeric terminal group is selected from among amines, thiols,amides, phosphates, sulphates, hydroxides, metals, alkanes, alkenes, andalkynes.

Also provided are compounds of Formula XXV and XXVI, as shown below:

where each Q′, G′, x, y, and terminal group are independently selectedas defined herein.

Also provided are compounds of Formula XXVII, XXVIII, XXIX, and XXX asshown below:

where each Q′, G′, R₂′, x, and terminal group are independently selectedas defined herein; and

a is selected from an integer of 1-25.

Also provided are compounds of Formula XXXI, XXXII, XXXIII, XXXIV, andXXXV, as shown below:

where each Q′, G′, x, y, and terminal group are independently selectedas defined; and

b is selected from an integer of 1-14.

Also provided are compounds of Formula XXXVI and XXXVII, as shown below:

where each Q′, G′, R₂′, x, y, and terminal group are independentlyselected as defined;

and c is selected from an integer of 1-14.

In certain embodiments, the G′ of Formula XXI-XXXVII is selected fromamong any group shown below:

where each Q′ and R₁′ are independently selected as defined herein.

In certain embodiments, each R₁′, G₁′, G₂′, and G′ group of any ofFormula XXI-XXXVII is independently selected from among a group shownbelow:

In certain embodiments, each R₁′, G₁′, G₂′, and G′ group of any ofFormula XXI-XXXVII is independently selected from among a group shownbelow:

In certain embodiments, each R₁′, G₁′, G₂′, and G′ group of any ofFormula XXI-XXXVII is independently selected from among a group as shownbelow:

where each Q′ is independently selected from among O, S, Se, or NH.

In certain embodiments, each R₁′, G₁′, G₂′, and G′ group of any ofFormula XXI-XXXVII is independently selected from among a group as shownbelow:

where each Q′ is independently selected from among O, S. Se, or NH.

In certain embodiments, each R₁′, G₁′, G₂′, and G′ group of any ofFormula XXI-XXXVII is independently selected from among a group as shownbelow:

where each Q′ is independently selected from among O, S, Se, or NH.

In certain embodiments, each R₁′, G₁′, G₂′, and G′ group of any ofFormula XXI-XXXVII is independently selected from among a group as shownbelow:

where each Q′ is independently selected from among O, S, Se, or NH.

In certain embodiments, each R₁′, G₁′, G₂′, and G′ group of any ofFormula XXI-XXXVII is independently selected from among a group as shownbelow:

Also provided is compound of Formula XXXVIII, as shown below:

where each Q′, G′, x, y, and terminal group is independently selected asdefined herein; and e is selected from an integer of 2-8.

In various embodiments, the compounds of Formula XXXVIII can be a randomcopolymer, a block copolymer, alternating copolymer, or a graftcopolymer.

In one embodiment, the compound of Formula XXXVIII is a compound ofFormula XXXIX, as shown below:

where each Q′, G′, x, y, and terminal group are independently selectedas defined herein.

In certain embodiments, the compound of Formula XXXVIII is selected fromamong a compound of Formula XL, XLI, XLII, or XLIII, as shown below:

where each G′, x, y, and terminal group are independently selected asdefined herein.

In certain embodiments, a compound of Formula XXXVIII is selected fromamong a compound of Formula XL where Q′ is oxygen. In certainembodiments, a compound of Formula XXXVIII is selected from among acompound of Formula XLI where Q′ is sulfur. In certain embodiments, acompound of Formula XXXVIII is selected from among a compound of FormulaXLII, where Q′ is Se. In certain embodiments, a compound of FormulaXXXVIII is selected from among a compound of Formula XLIII, where Q′ isNH.

In certain embodiments, the compound of Formula XXXVIII is selected fromamong a compound of Formula XLIV, XLV, or XLVI, as shown below:

where each G′, x, y, and terminal group are independently selected asdefined herein.

In certain embodiments, a compound of Formula XXXVIII is selected fromamong a compound of Formula XLIV. In certain embodiments, a compound ofFormula XXXVIII is selected from among a compound of Formula XLV. Incertain embodiments, a compound of Formula XXXVIII is selected fromamong a compound of Formula XLVI.

H. Synthesis of Polymers of Formulas XXI-XLVI

Any method of polymerization can be used to produce the polymers ofFormulas XXI-XLVI. For example, polymers of Formulas XXI-XLVI can beprepared by step-reaction polymerization, ring-opening polymerization,or by chain-reaction addition polymerization. As shown below, a polymerof Formula XXXVIII can be prepared by ring-opening polymerization of alactone monomer and a carbonate monomer. The product of this reaction isa polymer of Formula XXXVIII where Q′ is 0, and G′ is benzyl.

where x, y, e, and terminal group are independently selected as definedherein.

Any method of ring opening polymerization can be used for this reaction.For example, the ring opening polymerization may be induced by heatingthe reaction. In one embodiment, the reaction is catalyzed by a metalcatalyst, such as Sn(oct)₂. The reaction can be performed neat, or inthe presence of a solvent, such as toluene, dichloromethane, or diethylether. Any ratio of monomers can be used. For example, the ratio ofcarbonate monomer to lactone monomer can be 1:1, 1:2, 1:3, 1:4, 1:5,1:6, 1:7, 1:8, 1:9, or 1:19.

Any lactone can be used for the polymerization shown above. As shownbelow, the lactone can be a four, five, six, or seven membered ring:

where x, y, e, and terminal group are independently selected as definedherein.

As shown above, Compound 17 is prepared by polymerizing a benzyloxyglycerol carbonate with oxetan-2-one. Compound 18 is prepared bypolymerizing a benzyloxy glycerol carbonate with dihydrofuran-2(3H)-one.Compound 19 is prepared by polymerizing a benzyloxy glycerol carbonatewith tetrahydro-2H-pyran-2-one. Compound 20 is prepared by polymerizinga benzyloxy glycerol carbonate with oxepan-2-one.

I. Chemical Modifications of Polymers of Formulas XXI-XLVI

Polymers of Formulas XXI-XLVI, wherein G′ is a protecting group, can befurther modified to contain various side chains and pendant groups. Forexample, G′ can be any protecting group known in the art. In someembodiments, G′ is a benzyl ether or benzylidene protecting group. Anymethod known in the art of adding a side chain or pendant group to apolymer can be used to modify the polymers of Formulas XXI-XLVI. forexample, a polymer of Formulas XXI-XLVI can be modified to contain aside group selected from among a straight or branched alkyl, cycloalkyl,aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl orfluorocarbon chain of 3-50 carbons, wherein the alkyl, cycloalkyl, aryl,olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl orfluorocarbon chain is optionally substituted internally or terminally byone or more hydroxyl, hydroxyether, carboxyl, carboxyester,carboxyamide, amino, mono- or di-substituted amino, thiol, thioester,sulfate, phosphate, phosphonate, or halogen substituents.

Other side chain groups can be selected from among poly(ethyleneglycol), poly(ethylene oxide), poly(hydroxyacid), a carbohydrate, aprotein, a polypeptide, an amino acid, a nucleic acid, a nucleotide, apolynucleotide, any DNA or RNA segment, a lipid, a polysaccharide, anantibody, a pharmaceutical agent, or any epitope for a biologicalreceptor. Additionally, a functional side chain can be incorporated intoa polymer of any one of Formulas XXI-XLVI, such as a photocrosslinkableor ionically crosslinkable group.

One method of modifying a polymer of Formula XXXVIII is shown below. Thebenzyl ether can be cleaved to afford a hydroxyl group. Any method ofcleaving a benzyl ether known in the art can be used for thistransformation. For example, the benzyl ether can be cleaved bycatalytic hydrogenation. The resulting hydroxyl group can be reactedwith reactants or reagents to produce the polymer of Formula XXXVIIIwith a non-hydrogen G′ group. Any method of reacting an alcohol known inthe art can be used for this transformation.

In the compounds shown above x, y, e, and the terminal group areindependently selected as defined herein.

As shown below, the polymer of Formula XXXVIII containing a hydroxylmoiety can be modified to yield a polymer with various G′ groups. Forexample, the alcohol can be reacted with a carboxylic acid, such asstearic acid, oleic acid, or myristic acid. In other embodiments, thealcohol is reacted with 6-benzyloxy-hexanoic acid, hexanedioic acidmonobenzyl ester, or fmoc-6-amino-hexanoic acid. In various embodiments,the G′ group is a carbonate, an ester, or an ether.

In the compounds shown above x, y, e, and the terminal group areindependently selected as defined herein; and g is selected from aninteger of 1-25.

As shown below, a polymer containing a hydroxyl moiety can be modifiedto produce a polymer with various groups. For example, the alcohol canbe reacted with a carboxylic acid, such as stearic acid, oleic acid, ormyristic acid. In other embodiments, the alcohol is reacted with abenzyloxy-alkyl acid, a alkyl acid monobenzyl ester, or a protectedamino-alkyl acid. The benzyloxy, monobenzyl, and fmoc protecting groupscan be removed by methods known in the art to produce an alcohol, acarboxylic acid, or an amine, respectively.

In the compounds shown above x, y, e, g, and the terminal group areindependently selected as defined herein.J. Methods of Forming Particles and Films

Various types of films and particles can be formed from polymers ofFormulas XX-XLVI. As shown below, various types of films and particles,such as micro- or nanoparticles, can be made from polymers of Formula XXand XXXVIII. Any of the polymeric films and particles described hereincan be made to incorporate bioactive, e.g., therapeutic, agents withinthe polymer structure to produce a polymer/agent complex. Any methodknown in the art can be used to form a polymer/agent complex from themonomers and polymers described herein.

In the compounds shown above, each Q, Q′, G, G′, n, R₂, x, y, e, andterminal group are independently selected as defined herein.

Methods of Making Films

The polymers described herein can be used to produce films usingtechniques known in the art. For example, as shown above, a polymer ofFormula XX or XXXVIII is dissolved in an organic solvent, e.g.,dichloromethane, tetrahydrofuran, toluene, or an aqueous solution anddeposited onto a solid surface, such as a glass surface. In certainembodiments, the polymer is dissolved in a solvent along with an agent,such as 10-hydroxycamptothecin, and deposited onto a solid surface, suchas a glass surface. The solvent is then allowed to evaporate to afford apolymeric film either at ambient temperature or pressure, or at elevatedor reduced temperatures and/or pressures. In certain embodiments, thepolymer solution is deposited onto the solid surface using a syringe,e.g., a microsyringe. In other embodiments, the polymer solution isdeposited onto the solid surface, e.g., glass, mica, polymer, collagen,pericardium, TEFLON®, metal, metal alloy, ceramic or an oxide, using aspraying device, such as an aerosol device. For example, filmscontaining a polymer of Formula XX or XXXVIII can be formed bydissolving the polymer in an organic or aqueous solution, or a mixtureof organic and aqueous solutions, and applying the solution to asurface.

In other embodiments, films containing a polymer of Formula XX orXXXVIII are formed by melting the polymer. The melted polymer can beapplied to a solid surface, such as glass. In other embodiments, thepolymer is applied to a solid surface and is then melted to form apolymeric film.

In certain embodiments, multi-layered films are prepared. For example, apolymer is deposited onto a solid surface as described above to producea film. A second polymeric solution is then deposited onto the firstfilm. Polymer films of 1, 2, 3, 4, 5, and 6, or more layers can beproduced by this method. In other embodiments, each polymer film isproduced from a polymer of Formula XX or XXXVIII. In another embodiment,1, 2, or 3 of the layers include a polymer of Formula XX or XXXVIII, andeither 1, 2, or 3 other layers include a different polymer, such aspoly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid),polycaprolactone, poly(trimethylene carbonate), polyester,polycarbonate, or polyamide.

The various layers or fillers can be selected to dissolve or biodegradeat different rates to produce devices in which different agents areincluded in different layers and are released at different rates. Forexample, a first agent can be included in a first surface layer designedto provide a rapid release, e.g., within a few hours or days, and asecond agent can be included in a second layer designed to provide anextended release profile, e.g., 1 week, 2, 3, 4, 5 weeks, or even more.Alternatively, an other surface layer can be designed not to release anyagent, but to mearly delay release of agents in subsequent layers.

In certain embodiments, a patterned polymer film is prepared by using amicroprinter or a microsyringe. For example, a microprinter ormicrosyringe can be used to deposit a solution containing a polymer ofFormula XX or XXXVIII onto a solid surface, such as a glass surface. Themicroprinter or microsyringe deposits the solution in a controlledmanner to form patterns such as stripes and/or dots. The solvent isremoved by evaporation. This method can be performed with more than onepolymer simultaneously. A solution containing a polymer of Formula XX orXXXVIII and an agent, such as 10-hydroxycamptothecin, may be depositedonto a solid surface by this technique to afford a patterned agentcontaining film. Such patterned films can deliver agents to specificbiological areas and tissues, as determined by the specific pattern ofagent loaded within a film.

Methods of Making Particles

The polymers described herein can be used to produce micro- ornanoparticles using methods known in the art. For example, a water inoil emulsion technique is described by Edlund and co-workers (see Edlundet al., Adv. Polymer Sci., 157:67-112, 2001; and Wang et al., Chem.Pharm. Bull., (Tokyo) 44:1935, 1996). Briefly, a polymer is dissolved indichloromethane using a vortexing device. In certain embodiments, thepolymer is dissolved in dichloromethane along with an agent, such aspaclitaxel. The solution is placed in a 5% polyvinyl alcohol surfactantand vortexed (or sonicated using a probe tip sonicator) and stirred for16 hours to produce microparticles. The microparticles are collected andwashed with distilled/deionized water and lyophilized.

To produce nanoparticles, one can for example, use a miniemulsionpolymerization method (see, e.g., Landfester et al., Macromolecules,32:5222-8, 1999).

Briefly, a monomer as described herein and a free-radical initiator(such as Cl₂, 2,2′-azobis(2-methylpropionitrile) (AIBN), ordi-t-butylperoxide) are dissolved in a solvent, such as hexane, benzene,toluene, diethyl ether, chloroform, ethyl acetate, dichloromethane,1,4-dioxane, tetrahydrofuran (THF), acetone, acetonitrile (MeCN),dimethylformamide (DMF), or dimethyl sulfoxide. In certain embodiments,an agent, such as paclitaxel is also dissolved in the solvent. Thesolvent is removed via rotary evaporation until a viscous mixtureremains. The viscous mixture is mixed with a stabilizing surfactant,such as a solution of sodium dodecyl sulfate, in a buffer solution. Thismixture is sonicated for 1 hour (1 second pulses with a 2 second delay)with 30 W of power, which forms the miniemulsion and allows the solventto evaporate. The miniemulsion is transferred into atemperature-controlled oil bath and stirred at 65° C. for 2 hours toinitiate the free-radical polymerization. Optionally, the resultingpolymeric nanospheres are dialyzed, e.g., against 5 mM pH 8 phosphatebuffer, acetate buffer, bicarbonate buffer, or sodium citrate buffer,e.g., over two days, to remove excess surfactant and salts.

Alternatively, nanoparticles can be produced by photoinitiation. Forexample, a monomer as described herein can be dissolved in a solvent,such as hexane, benzene, toluene, diethyl ether, chloroform, ethylacetate, dichloromethane, 1,4-dioxane, tetrahydrofuran (THF), acetone,acetonitrile (MeCN), dimethylformamide (DMF), or dimethyl sulfoxide. Incertain embodiments, an agent, such as paclitaxel is also dissolved inthe solvent. The solvent is removed via rotary evaporation until aviscous mixture remains. The viscous mixture is mixed with a stabilizingsurfactant solution, such as sodium dodecyl sulfate, in a buffersolution. The mixture is then sonicated for 30 minutes (1 second pulseswith a 2 second delay) with 30 W of power, forming the miniemulsion andallowing the solvent to partially evaporate. Eosin Y and1-vinyl-2-pyrrolidone are added to the emulsion. The mixture is thenexposed to light from a source such as a mercury arc lamp while thesolution is stirred vigorously. The resulting particles are stirredovernight while open to the air to allow any remaining solvent toevaporate. Optionally, the polymeric nanoparticles are then dialyzedagainst a buffer solution to remove excess surfactant and salts.

Polymeric particles can also be prepared by a precipitation method. Forexample, a polymer of Formula XXXVIII is dissolved in a solvent, such asdichloromethane, along with an agent, such as paclitaxel. The solutionis added to an aqueuous surfactant solution, such as sodium dodecylsulfate in water. The resulting mixture is sonicated to produce anemulsion. The mixture is stirred while open to the atmosphere toevaporate the excess solvent, such as dichoromethane. The resultingparticles are collected and optionally dialyzed using a membrane with amolecular weight cutoff to remove excess surfactant.

In some embodiments, the diameter of the particles formed is between 1nm and 50 microns, e.g., between 10 nm and 1 micron, between 50 nm and 1micron, between 100 nm and 500 nm, or between 1 and 50 microns.

Encapsulation of an Agent Within Polymeric Particles

Any method known in the art for encapsulating an agent within apolymeric particle can be used to form a polymer/agent complex. Forexample, an oil emulsion technique is used to form paclitaxel containingparticles of Formula XX. A polymer of Formula XX can be dissolved in asolvent, such as dichloromethane, in the presence of an agent, such aspaclitaxel. The polymer/paclitaxel solution is vortexed. A surfactantsolution, such as 5% polyvinyl alcohol, is added to thepolymer/paclitaxel solution, and the resulting solution is vortexed forabout 15 minutes followed by stirring for about 16 hours. The resultingparticles are collected, washed with water, and lyophilized. In certainembodiments, the encapsulation efficiency of paclitaxel by the particlesusing this technique is between 30-99%. In another embodiment, theencapsulation efficiency of paclitaxel by the particles using thistechnique is between 60-75%.

Agents that can be Incorporated into Polymeric Films and Particles

Any agent can be incorporated within the polymer films and particlesdescribed herein. For example, a polymer film or particle describedherein can incorporate a pharmaceutical agent selected from among (1)nonsteroidal anti-inflammatory drugs (NSAIDs) analgesics, such asdiclofenac, ibuprofen, ketoprofen, and naproxen; (2) opiate agonistanalgesics, such as codeine, fentanyl, hydromorphone, and morphine; (3)salicylate analgesics, such as aspirin (ASA) (enteric coated ASA); (4)H₁-blocker antihistamines, such as clemastine and terfenadine; (5)H₂-blocker antihistamines, such as cimetidine, famotidine, nizadine, andranitidine; (6) anti-infective agents, such as mupirocin; (7)antianaerobic anti-infectives, such as chloramphenicol and clindamycin;(8) antifungal antibiotic anti-infectives, such as amphotericin b,clotrimazole, fluconazole, and ketoconazole; (9) macrolide antibioticanti-infectives, such as azithromycin and erythromycin; (10)miscellaneous beta-lactam antibiotic anti-infectives, such as aztreonamand imipenem; (11) penicillin antibiotic anti-infectives, such asnafcillin, oxacillin, penicillin G, and penicillin V; (12) quinoloneantibiotic anti-infectives, such as ciprofloxacin and norfloxacin; (13)tetracycline antibiotic anti-infectives, such as doxycycline,minocycline, and tetracycline; (14) antituberculosis antimycobacterialanti-infectives such as isoniazid (INH), and rifampin; (15)antiprotozoal anti-infectives, such as atovaquone and dapsone; (16)antimalarial antiprotozoal anti-infectives, such as chloroquine andpyrimethamine; (17) anti-retroviral anti-infectives, such as ritonavirand zidovudine; (18) antiviral anti-infective agents, such as acyclovir,ganciclovir, interferon alpha, and rimantadine; (19) alkylatingantineoplastic agents, such as carboplatin and cisplatin; (20)nitrosourea alkylating antineoplastic agents, such as carmustine (BCNU);(21) antimetabolite antineoplastic agents, such as methotrexate; (22)pyrimidine analog antimetabolite antineoplastic agents, such asfluorouracil (5-FU) and gemcitabine; (23) hormonal antineoplastics, suchas goserelin, leuprolide, and tamoxifen; (24) natural antineoplastics,such as aldesleukin, interleukin-2, docetaxel, etoposide (VP-16),interferon alpha, paclitaxel, and tretinoin (ATRA); (25) antibioticnatural antineoplastics, such as bleomycin, dactinomycin, daunorubicin,doxorubicin, and mitomycin; (26) vinca alkaloid natural antineoplastics,such as vinblastine and vincristine; (27) autonomic agents, such asnicotine; (28) anticholinergic autonomic agents, such as benztropine andtrihexyphenidyl; (29) antimuscarinic anticholinergic autonomic agents,such as atropine and oxybutynin; (30) ergot alkaloid autonomic agents,such as bromocriptine; (31) cholinergic agonist parasympathomimetics,such as pilocarpine; (32) cholinesterase inhibitor parasympathomimetics,such as pyridostigmine; (33) alpha-blocker sympatholytics, such asprazosin; (34) beta-blocker sympatholytics, such as atenolol; (35)adrenergic agonist sympathomimetics, such as albuterol and dobutamine;(36) cardiovascular agents, such as aspirin (ASA), plavix (Clopidogrelbisulfate) etc; (37) beta-blocker antianginals, such as atenolol andpropranolol; (38) calcium-channel blocker antianginals, such asnifedipine and verapamil; (39) nitrate antianginals, such as isosorbidedinitrate (ISDN); (40) cardiac glycoside antiarrhythmics, such asdigoxin; (41) class I anti-arrhythmics, such as lidocaine, mexiletine,phenyloin, procainamide, and quinidine; (42) class II antiarrhythmics,such as atenolol, metoprolol, propranolol, and timolol; (43) class IIIantiarrhythmics, such as amiodarone; (44) class IV antiarrhythmics, suchas diltiazem and verapamil; (45) alpha-blocker antihypertensives, suchas prazosin; (46) angiotensin-converting enzyme inhibitor (ACEinhibitor) antihypertensives, such as captopril and enalapril; (47) betablocker antihypertensives, such as atenolol, metoprolol, nadolol, andpropanolol; (48) calcium-channel blocker antihypertensive agents, suchas diltiazem and nifedipine; (49) central-acting adrenergicantihypertensives, such as clonidine and methyldopa; (50) diurecticantihypertensive agents, such as amiloride, furosemide,hydrochlorothiazide (HCTZ), and spironolactone; (51) peripheralvasodilator antihypertensives, such as hydralazine and minoxidil; (52)antilipemics, such as gemfibrozil and probucol; (53) bile acidsequestrant antilipemics, such as cholestyramine; (54) HMG-CoA reductaseinhibitor antilipemics, such as lovastatin and pravastatin; (55)inotropes, such as aminone, dobutamine, and dopamine; (56) cardiacglycoside inotropes, such as digoxin; (57) thrombolytic agents orenzymes, such as alteplase (TPA), anistreplase, streptokinase, andurokinase; (58) dermatological agents, such as colchicine, isotretinoin,methotrexate, minoxidil, tretinoin (ATRA); (59) dermatologicalcorticosteroid anti-inflammatory agents, such as betamethasone anddexamethasone; (60) antifungal topical antiinfectives, such asamphotericin B, clotrimazole, miconazole, and nystatin; (61) antiviraltopical anti-infectives, such as acyclovir; (62) topicalantineoplastics, such as fluorouracil (5-FU); (63) electrolytic andrenal agents, such as lactulose; (64) loop diuretics, such asfurosemide; (65) potassium-sparing diuretics, such as triamterene; (66)thiazide diuretics, such as hydrochlorothiazide (HCTZ); (67) uricosuricagents, such as probenecid; (68) enzymes such as RNase and DNase; (69)immunosupressive agents, such as cyclosporine, steroids, methotrexatetacrolimus, sirolimus, rapamycin; (70) antiemetics, such asprochlorperazine; (71) salicylate gastrointestinal anti-inflammatoryagents, such as sulfasalazine; (72) gastric acid-pump inhibitoranti-ulcer agents, such as omeprazole; (73) H₂-blocker anti-ulceragents, such as cimetidine, famotidine, nizatidine, and ranitidine; (74)digestants, such as pancrelipase; (75) prokinetic agents, such aserythromycin; (76) opiate agonist intravenous anesthetics such asfentanyl; (77) hematopoietic antianemia agents, such as erythropoietin,filgrastim (G-CSF), and sargramostim (GM-CSF); (78) coagulation agents,such as antihemophilic factors 1-10 (AHF 1-10); (79) anticoagulants,such as warfarin, heparin, and argatroban; (80) growth receptorinhibitors, such as erlotinib and gefetinib; (82) abortifacients, suchas methotrexate; (83) antidiabetic agents, such as insulin; (84) oralcontraceptives, such as estrogen and progestin; (85) progestincontraceptives, such as levonorgestrel and norgestrel; (86) estrogenssuch as conjugated estrogens, diethylstilbestrol (DES), estrogen(estradiol, estrone, and estropipate); (87) fertility agents, such asclomiphene, human chorionic gonadatropin (HCG), and menotropins; (88)parathyroid agents such as calcitonin; (89) pituitary hormones, such asdesmopressin, goserelin, oxytocin, and vasopressin (ADH); (90)progestins, such as medroxyprogesterone, norethindrone, andprogesterone; (91) thyroid hormones, such as levothyroxine; (92)immunobiologic agents, such as interferon beta-1b and interferongamma-1b; (93) immunoglobulins, such as immune globulin IM, IMIG, IGIMand immune globulin IV, IVIG, IGIV; (94) amide local anesthetics, suchas lidocaine; (95) ester local anesthetics, such as benzocaine andprocaine; (96) musculoskeletal corticosteroid anti-inflammatory agents,such as beclomethasone, betamethasone, cortisone, dexamethasone,hydrocortisone, and prednisone; (97) musculoskeletal anti-inflammatoryimmunosuppressives, such as azathioprine, cyclophosphamide, andmethotrexate; (98) musculoskeletal nonsteroidal anti-inflammatory drugs(NSAIDs), such as diclofenac, ibuprofen, ketoprofen, ketorlac, andnaproxen; (99) skeletal muscle relaxants, such as baclofen,cyclobenzaprine, and diazepam; (100) reverse neuromuscular blockerskeletal muscle relaxants, such as pyridostigmine; (101) neurologicalagents, such as nimodipine, riluzole, tacrine and ticlopidine; (102)anticonvulsants, such as carbamazepine, gabapentin, lamotrigine,phenyloin, and valproic acid; (103) barbiturate anticonvulsants, such asphenobarbital and primidone; (104) benzodiazepine anticonvulsants, suchas clonazepam, diazepam, and lorazepam; (105) anti-parkisonian agents,such as bromocriptine, levodopa, carbidopa, and pergolide; (106)anti-vertigo agents, such as meclizine; (107) opiate agonists, such ascodeine, fentanyl, hydromorphone, methadone, and morphine; (108) opiateantagonists, such as naloxone; (109) beta-blocker anti-glaucoma agents,such as timolol; (110) miotic anti-glaucoma agents, such as pilocarpine;(111) ophthalmic aminoglycoside antiinfectives, such as gentamicin,neomycin, and tobramycin; (112) ophthalmic quinolone anti-infectives,such as ciprofloxacin, norfloxacin, and ofloxacin; (113) ophthalmiccorticosteroid anti-inflammatory agents, such as dexamethasone andprednisolone; (114) ophthalmic nonsteroidal anti-inflammatory drugs(NSAIDs), such as diclofenac; (115) antipsychotics, such as clozapine,haloperidol, and risperidone; (116) benzodiazepine anxiolytics,sedatives and hypnotics, such as clonazepam, diazepam, lorazepam,oxazepam, and prazepam; (117) psychostimulants, such as methylphenidateand pemoline; (118) antitussives, such as codeine; (119)bronchodilators, such as theophylline; (120) adrenergic agonistbronchodilators, such as albuterol; (121) respiratory corticosteroidanti-inflammatory agents, such as dexamethasone; (122) antidotes, suchas flumazenil and naloxone; (123) heavy metal antagonists/chelatingagents, such as penicillamine; (124) deterrent substance abuse agents,such as disulfuram, naltrexone, and nicotine; (125) withdrawal substanceabuse agents, such as bromocriptine; (126) minerals, such as iron,calcium, and magnesium; (127) vitamin B compounds, such ascyanocobalamin (vitamin B12) and niacin (vitamin B3); (128) vitamin Ccompounds, such as ascorbic acid; (129) vitamin D compounds, such ascalcitriol; (130) vitamin A, vitamin E, and vitamin E compounds; (131)poisons, such as racin; (132) anti-bleeding agents, such as protamine;(133) antihelminth anti-infectives, such as metronidazole; and (134)sclerosants such as talc, alcohol, and doxycyclin.

In addition to the foregoing, the following less common drugs can alsobe used: chlorhexidine; estradiol cypionate in oil; estradiol valeratein oil; flurbiprofen; flurbiprofen sodium; ivermectin; levodopa;nafarelin; and somatropin. Further, the following drugs can also beused: recombinant beta-glucan; bovine immunoglobulin concentrate; bovinesuperoxide dismutase; the formulation comprising fluorouracil,epinephrine, and bovine collagen; recombinant hirudin (r-Hir), HIV-1immunogen; human anti-TAC antibody; recombinant human growth hormone(r-hGH); recombinant human hemoglobin (r-Hb); recombinant humanmecasermin (r-IGF-1); recombinant interferon beta-1a; lenograstim(G-CSF); olanzapine; recombinant thyroid stimulating hormone (r-TSH);and topotecan. Further still, the following intravenous products can beused: acyclovir sodium; aldesleukin; atenolol; bleomycin sulfate, humancalcitonin; salmon calcitonin; carboplatin; carmustine; dactinomycin,daunorubicin HCl; docetaxel; doxorubicin HCl; epoetin alpha; etoposide(VP-16); fluorouracil (5-FU); ganciclovir sodium; gentamicin sulfate;interferon alpha; leuprolide acetate; meperidine HCl; methadone HCl;methotrexate sodium; paclitaxel; ranitidine HCl; vinblastin sulfate; andzidovudine (AZT).

Further specific examples of useful pharmaceutical agents from the abovecategories include: (a) anti-neoplastics such as androgen inhibitors,antimetabolites, cytotoxic agents, receptor inhibitors, andimmunomodulators; (b) anti-tussives such as dextromethorphan,dextromethorphan hydrobromide, noscapine, carbetapentane citrate, andchlorphedianol hydrochloride; (c) antihistamines such aschlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate,doxylamine succinate, and phenyltoloxamine citrate; (d) decongestantssuch as phenylephrine hydrochloride, phenylpropanolamine hydrochloride,pseudoephedrine hydrochloride, and ephedrine; (e) various alkaloids suchas codeine phosphate, codeine sulfate and morphine; (f) mineralsupplements such as potassium chloride, zinc chloride, calciumcarbonates, magnesium oxide, and other alkali metal and alkaline earthmetal salts; (g) ion exchange resins such as cholestryramine; (h)anti-arrhythmics such as N-acetylprocainamide; (i) antipyretics andanalgesics such as acetaminophen, aspirin and ibuprofen; (j) appetitesuppressants such as phenyl-propanolamine hydrochloride or caffeine; (k)expectorants such as guaifenesin; (l) antacids such as aluminumhydroxide and magnesium hydroxide; (m) biologicals such as peptides,polypeptides, proteins and amino acids, hormones, interferons orcytokines, and other bioactive peptidic compounds, such as interleukins1-18 including mutants and analogues, RNase, DNase, luteinizing hormonereleasing hormone (LHRH) and analogues, gonadotropin releasing hormone(GnRH), transforming growth factor-β. (TGF-beta), fibroblast growthfactor (FGF), tumor necrosis factor-alpha & beta (TNF-alpha & beta),nerve growth factor (NGF), growth hormone releasing factor (GHRF),epidermal growth factor (EGF), fibroblast growth factor homologousfactor (FGFHF), hepatocyte growth factor (HGF), insulin growth factor(IGF), invasion inhibiting factor-2 (IIF-2), bone morphogenetic proteins1-7 (BMP 1-7), somatostatin, thymosin-alpha-1, gamma-globulin,superoxide dismutase (SOD), complement factors, hGH, tPA, calcitonin,ANF, EPO and insulin; (n) anti-infective agents such as antifungals,anti-virals, antihelminths, antiseptics and antibiotics; and (m) oxygen,hemoglobin, nitric or sliver oxide.

Non-limiting examples of broad categories of useful pharmaceuticalagents include the following therapeutic categories: anabolic agents,anesthetic agents, antacids, anti-asthmatic agents, anticholesterolemicand anti-lipid agents, anti-coagulants, anti-convulsants,anti-diarrheals, antiemetics, anti-infective agents, anti-inflammatoryagents, anti-manic agents, anti-nauseants, antineoplastic agents,anti-obesity agents, anti-pyretic and analgesic agents, anti-spasmodicagents, anti-thrombotic agents, anti-uricemic agents, anti-anginalagents, antihistamines, anti-tussives, appetite suppressants,biologicals, cerebral dilators, coronary dilators, decongestants,diuretics, diagnostic agents, erythropoietic agents, expectorants,gastrointestinal sedatives, hyperglycemic agents, hypnotics,hypoglycemic agents, ion exchange resins, laxatives, mineralsupplements, mucolytic agents, neuromuscular drugs, peripheralvasodilators, psychotropics, sedatives, stimulants, thyroid andanti-thyroid agents, uterine relaxants, vitamins, and prodrugs. Examplesof specific drugs that can be used include: asparaginase, bleomycin,busulfan, capecitabine, carboplatin, carmustine, chlorambucil,cisplatin, cyclophosphamide, cytarabine, dacarbizine, dactinomycin,daunorubicin, dexrazoxane, docetaxel, doxorubicin, etoposide,floxuridine, fludarabine, fluoruracil, gemcitabine, hydroxyurea,idarubicin, ifosfamide, irinotecan, lomustine, mechlorethamine,melphalan, mercaptopurine, methotrexate, mitomycin, mitotane,mitoxantrone, paclitaxel, pentostatin, plicamycin, premextredprocarbazine, rituximabe, streptozocin, teniposid, thioguanine,thiotepa, vinplastine, vinchristine, and vinorelbine. The currentlypreferred drugs for lung cancer treatment is paclitaxel, pemetrexed,10-hydrocamptothecin, irinotecan, erlotinibil/gefetinib or derivates ofthese molecules.

Examples of anticancer, antineoplastic agents are camptothecins. Thesedrugs are antineoplastic by virtue of their ability to inhibittopoisomerase I. Camptothecin is a plant alkaloid isolated from treesindigenous to China and analogs thereof such as 9-aminocamptothecin,9-nitrocamptothecin, 10-hydroxycamptothecin,10,11-methylenedioxycamptothecin,9-nitro-10,11-methylenehydroxycamptothecin,9-chloro-10,11-methylenehydroxycamptothecin,9-amino-10,11-methylenehydroxycamptothecin,7-ethyl-10-hydroxycamptothecin (SN-38), topotecan, DX-8951, Lurtotecan(GII147221C), and other analogs (collectively referred to herein ascamptothecin drugs) are presently under study worldwide in researchlaboratories for treatment of colon, breast, and other cancers.

Additionally, the pharmaceutical agent can be a radiosensitizer, such asmetoclopramide, sensamide or neusensamide (manufactured by Oxigene);profiromycin (made by Vion); RSR13 (made by Allos); THYMITAQ® (made byAgouron), etanidazole or lobenguane (manufactured by Nycomed);gadolinium texaphrin (made by Pharmacyclics); BuDR/Broxine (made byNeoPharm); IPdR (made by Sparta); CR2412 (made by Cell Therapeutic); LlX(made by Terrapin); agents that minimize hypoxia, and the like.

The agent can be selected from a biologically active substance. Thebiologically active substance can be selected from the group consistingof peptides, poly-peptides, proteins, amino acids, polysaccharides,growth factors, hormones, anti-angiogenesis factors, interferons orcytokines, elements, and pro-drugs. In useful embodiments, thebiologically active substance is a therapeutic drug or pro-drug, mostpreferably a drug selected from the group consisting of chemotherapeuticagents and other antineoplastics such as paclitaxel, antibiotics,anti-virals, antifungals, anesthetics, antihelminths,anti-inflammatories, and anticoagulants. In certain useful embodiments,the therapeutic drug or pro-drug is selected from the group consistingof chemotherapeutic agents and other antineoplastics such as paclitaxel,carboplatin and cisplatin; nitrosourea alkylating antineoplastic agents,such as carmustine (BCNU); fluorouracil (5-FU) and gemcitabine; hormonalantineoplastics, such as goserelin, leuprolide, and tamoxifen; receptorinhibitors such as erlotinib, gefetinib, sutent or anti-ckit inhibitors,such as GLEEVEC®; natural antineoplastics, such as aldesleukin,interleukin-2, docetaxel, etoposide (VP-16), interferon alpha,paclitaxel, and tretinoin (ATRA).

In another embodiment, the biologically active substance is a nucleicacid sequence. The nucleic acid sequence can be selected from among anyDNA or RNA sequence. In certain embodiments, the biologically activesubstance is a DNA sequence that encodes a genetic marker selected fromamong luciferase gene, β-galactosidase gene, resistance, neomycinresistance, and chloramphenicol acetyl transferase. In certainembodiments, the biologically active substance is a DNA sequence thatencodes a lectin, a mannose receptor, a sialoadhesin, or a retroviraltransactivating factor. In certain embodiments, the biologically activesubstance is a DNA sequence that encodes a RNA selected from the groupconsisting of a sense RNA, an antisense RNA, siRNA and a ribozyme.

Biologically active agents amenable for use with the new polymersdescribed herein include, without limitation, medicaments; vitamins;mineral supplements; substances used for the treatment, prevention,diagnosis, cure or mitigation of disease or illness; or substances whichaffect the structure or function of the body; or pro-drugs, which becomebiologically active or more active after they have been placed in apredetermined physiological environment. Useful active agents amenablefor use in the new compositions include growth factors, such astransforming growth factors (TGFs), fibroblast growth factors (FGFs),platelet derived growth factors (PDGFs), epidermal growth factors(EGFs), connective tissue activated peptides (CTAPs), osteogenicfactors, and biologically active analogs, fragments, and derivatives ofsuch growth factors. Members of the transforming growth factor (TGF)supergene family, which are multifunctional regulatory proteins, arepreferred. Members of the TGF supergene family include thebeta-transforming growth factors (for example, TGF-b1, TGF-b2, andTGF-b3); bone morphogenetic proteins (for example, BMP-1, BMP-2, BMP-3,BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, and BMP-9); heparin-binding growthfactors (for example, fibroblast growth factor (FGF), epidermal growthfactor (EGF), platelet-derived growth factor (PDGF), and insulin-likegrowth factor (IGF)); inhibins (for example, Inhibin A, Inhibin B);growth differentiating factors (for example, GDF-1); and activins (forexample, Activin A, Activin B, and Activin AB).

K. Applications for Polymer/Agent Compositions

The polymers provided herein can be utilized to promote healing or treator inhibit disease by targeting drug delivery to local and regionalareas. The polymers provided herein can also be used for a variety ofapplications including, but not limited to, production of micro- andnanoparticles, films, tissue scaffolding, coatings, sutures, andorthopedic materials. The polymers can also be used in various cosmeticapplications, such as tissue augmentation. Such materials can be used torepair an injured tissue, organ, bone, or genetic defect. Other uses ofthe polymers provided herein include treatment of early, late, orpreviously treated malignancies or to inhibit recurrence of cancers thathave been surgically removed or locally treated, avoidance oflocoregional lymph node metastasis, augmentation of local wound healingand decrease in infection, manipulation of structure and abnormal scarformation, and for the treatment of post-operative pain.

In some embodiments, the polymers provided herein are used to treatcancer. For example, the polymers provided herein can be used to treatlung, colon, prostate, pancreas, or breast cancer. They could also beused with bone marrow transplantation to target residual tumor cells inthe graft, such as lympohomas and leukemias. The polymeric particles canbe injected or infused into or around inoperable tumors to locallydeliver drugs, such as chemotherapy or sensitizers, or injected orinfused near the site of the operation incision to deliver agents suchas antibiotics, anesthetics, or growth or healing factors, therebyavoiding side effects associated with systemic delivery. The polymericparticles provided herein can be administered at a site of surgery withthe intent of the particles being carried by the lymph fluid tolocoregional nodes. The particles can become trapped at the lymph nodes,allowing delivery of agents to tumor cells that also commonly migrate tolymph nodes. Cells that commonly migrate to lymph nodes include tumorcells and immune cells such as T cells or dendritic cells, and thusdirect presentation of antigen by the particles can be utilized toenhance the immune system. Thus, the particles can be used to treattumors systemically either by targeting the tumor cells directly or byupregulating the immune system to fight the tumor.

The polymeric particles and films provided herein can also beadministered to sites where tumor regrowth is likely to occur. Theparticles and films can be administered to areas where, as a consequenceof disease, such as COPD or inflammatory bowl disease, or systemicchemotherapy, poor healing will result in major complications. Inaddition, the particles and films can be administered to the margins ofa surgical excision or resection, or to sites following local ablativetherapy. For such applications, the polymeric particles are prepared toadhere to the surgical margin or be retained within the confines andperimeter of the mass. In other embodiments, the particles or filmsadhere to the pericardium, cartilage, or collagen for the delivery ofanti-cancer or antineoplastic agents. In other embodiments, the filmscan be stapled, sutured, and/or glued in place at a site.

In other embodiments, the films and particles described herein can beused in cosmetic applications. In such an application, the swellingassociated with pH changes can be advantageously utilized. For example,many of the acrylate polymers described herein upon delivery to a tissuesite swell and increase in size and bulk, filling voids. Such polymerscan be used without any agents to fill wrinkles or to increase the sizeof tissue, e.g., in the lips or cheeks. Optionally, the polymers coulddeliver cosmetic agents such as BOTOX® and/or analgesics. The net resultof such a treatment could be, e.g., a smoothing of facial tissue. Insome embodiments, the polymers used for such an application are, e.g.,2a-6a and 9a and 10a.

Any method of adhering particles to biological tissue can be used forthis application. For example, the polymeric particles provided hereincan be coated with Pluronic F127. In another embodiment, the particlesare entrapped within a gel, hydrogel, adhesive, sealant or surgicalreinforcement strip made from pericardium, TEFLON®, plastic, or othermaterials or particles that can utilize a specific bound such asbiotin-avidin to increase there resident time at the implant site.

In addition, other types of surgery can benefit from the use of thepolymeric particles and films described herein. For example, films andparticles that contain antibiotics can be utilized for local delivery ata surgical site. The release rate of the antibiotics and/or analgesicscan be prolonged to reduce the risk of post-surgical infection, such asClostridium difficile infection. This method provides an alternative tothe use and risk of systemic antibiotics. The films and particles cancontain anesthetics, such as local amide anesthetics, IV narcotics, oranti-inflammatory agents, such as steroids or NSAIDS, to reduce thediscomfort of patients. The use of such polymeric materials can reducemorbidity secondary to delirium and constipation, decrease the length ofhospital stays for patients, and reduce overall health care costs.

In certain embodiments, the polymeric films and particles are in contactwith aqueous or organic solutions, or combinations thereof. The aqueoussolutions can be selected from among water, buffered aqueous media,saline, buffered saline, solutions of amino acids, solutions of sugars,solutions of vitamins, solutions of carbohydrates or combinations of anytwo or more thereof. The organic solutions can be selected from amongDMSO, ethanol, methanol, THF, dichloromethane, DMF, hexane or toluene orcombinations of any two or more thereof.

The polymeric particles and films can contain genetic materials, e.g.,nucleic acid sequences. Such materials can be used to transfect cells invitro, ex vivo, or in vivo. The polymeric particles and films cancontain a receptor recognizing a targeting moiety, allowing specificentrance into a cell or activation or inhibition of a cell receptor orsubsequent intracellular signaling or apopototic pathway. Thus, thepolymeric materials described herein can be used to deliver nucleic acidsequences to a cell or to deliver agents that can be transported to thenucleus of a cell or effect transcription or translation within a cell,such as steroids or specific transcription factors.

The methods of using the polymeric particles and films described hereincan be used separately or they can be combined with one or moretherapies to treat a single patient. For example, particles containingone type of therapeutic agent can be designed and delivered in a mannerthat results in the particles becoming entrapped at lymph nodes, whereasother particles or films that contain either the same or a differenttherapeutic agent can be applied to surgical margins or suture sites. Itshould also be recognized that other agents besides chemotherapeuticagents, e.g., cytokines, growth factors, and anti-inflammatory agents,can be used in these methods and combinations of particles containing avariety of chemotherapeutic or other agents can be employed to both killtumor, foster healing, and decrease pain.

The polymeric microparticles, nanoparticles, films, gels, and otherpolymer forms provided herein can be used for in vitro and in vivomanipulation of drug release kinetics. Depending upon the polymerselected, the rate of drug release can be delayed or immediate. Incertain embodiments, the polymers provided herein can be used forprolonged drug delivery after an initial period of quiescence to permitsurgical healing to occur. In other embodiments, the polymeric particlesprovided herein provide a dual mechanism of delivery where a drug isreleased from the particles and the particles swell to destabilize ordestroy the cell or cellular compartment (e.g., endosome).Alternatively, the particles can swell and become lodged, embedded, orotherwise immobilized at a certain target location due to the enlargedsize of the particle. For example, swelled particles can become lodgedor embedded within a cavity, node, tubule, bronchus, or capillary andcan be used to occlude blood flow as an embolization agent for bleeding,arteriovenous malformations, or tumor devascularization or can be usedto prevent airflow to a specific portion of the lung as for endoscopiclung volume reduction surgery, to cite only two examples of potentialuses of this property. Particle swelling can be triggered by pH changefrom an exogenous agent added to the polymer, a change within a cavityor vessel as can occur in a ischemic or infected tissue or cavity orwithin an intracellular compartment such as an endosome. Such particlescan also be manufactured to release agents that manipulate healing orfibrosis to facilitate permanent or temporary closure of the occludedlumen or cavity.

Certain embodiments of the invention are directed towards polymericfilms that are designed to deliver chemotherapeutic agents locally atsurgical sites, with incorporation into the resection margin. Thesefilms are used, e.g., in the treatment of cancer patients, wheredelivering drugs locally has the advantage of avoiding side effectsassociated with systemic drug delivery. These films allow the deliveryof agents at local concentrations that could not otherwise be achieveddue to drug toxicity. The films can release agents at the site ofsurgery and the released agents can diffuse to areas of close proximityto the implantation site and to the site of metastatic tumor growth. Theimplanted polymeric films can deliver one or more anti-cancer agents,e.g., as described herein, that will act upon cancer or metastatic cellsremaining at the surgical margins after tumor excision is performed.Thus, the films can reduce the incidence of tumor recurrence at aresection margin after removel of cancerous tissue.

An advantage of the films provided herein is the ability to cover largerareas uniformly. For example, the polymeric films can cover the chestwall to treat diseases such as mesothelioma or in other body cavitiesfor diseases such as sarcomas. In addition, the polymeric films canincorporate local anesthetics or IV narcotics and be applied along anentire surgical incision for peri-operative analgesia, or incorporategrowth factors, anti-inflammatory agents in order to maipulate woundhealing and prevent hypertrophic scar or stricture formation.

Polymeric films containing a single or multiple agents can be applied toa solid surface in a controlled manner to form patterns such as stripesand dots. Single or multiple agents can be incorporated in any patternto achieve precise therapeutic delivery of multiple agentssimultaneously. More than one type of polymer film can be used tofurther tune or control the release of the drug. A further embodiment ofthe invention is the use of multi-layer films to alter the release ofthe agent(s).

For example, a film composed of a polyester-co-carbonate of 80:20caproic acid and glycerol-stearic acid can be loaded with a drug, suchas taxol, camptothecin, or pemetrexed. The film can then be coated withanother polymer of the same or different composition that does notcontain the drug, forming a multi-layered film. The top polymer layer,which does not have the drug, acts as a sacrificial layer that firstinhibits the release of the drug from the underlying film, but as thetop layer degrades, the bottom layer starts to release the drug. In thisfashion, delayed and controlled release can occur and can be utilized toallow initial wound healing to occur before delivery of chemotherapywhich can inhibit wound healing, as one example. Alternatively,different drugs can be released sequentially and either enhance orprolong the effect of the other drug or protect “normal” cells from thetoxic effects of the second drug or to rescue cells from the effects ofa second agent, for example pre-treatment with folate can limit toxicityof normal cells to anti-folate chemotherapies and yet tumor cells remainsusceptible.

The polymers provided herein can be used to deliver any agent. The agentcan be in any pharmaceutically acceptable form, includingpharmaceutically acceptable salts. A large number of pharmaceuticalagents are known in the art and are amenable for use in thepharmaceutical compositions of the polymeric materials described herein.Acceptable agents are described elsewhere herein, and include, but arenot limited to, chemotherapeutic agents, such as radiosensitizers,receptor inhibitors and agonists or other anti-neoplastic agent; immunemodulators and bioactive agents, such as cytokines, growth factors orsteroids with or without the co-incorporation of tumor or pathogenantigens to increase the anti-neoplastic response as a means of vaccinedevelopment; local anesthetic agents; antibiotics; or nucleic acids as ameans of local gene therapy.

The biologically active substances and agents are used in amounts thatare therapeutically effective. While the effective amount of abiologically active substance will depend on the particular materialbeing used, amounts of the biologically active substance from about 1%to about 65% can be desirable. Lesser amounts can be used to achieveefficacious levels of treatment for certain biologically activesubstances.

The amount of drug delivered per area of film or per particle willdepend on the therapeutic range of the drug, its toxicity when deliveredlocally, and the clinical characteristics of the patient being treated.The number of particles or amount of film delivered to a site isselected depending on factors such as 1) the amount of agent deliveredper particle, 2) the therapeutic range of the agent, 3) the localtoxicity of the agent, and 4) the clinical characteristics of thepatient being treated. The development of dosages based on theseparameters is routinely performed by those skilled in the art ofpharmacology and clinical medicine. For example, between 1×10⁴ and 1×10⁹particles/cm can be administered to a biological area.

The release kinetics of a given polymer film or particle can befine-tuned and adjusted by varying the ratio of monomer units and/or bymodifying the side chains of a given copolymer. In this manner, a familyof copolymers with varying release kinetics can be used to accommodatethe delivery of several different drugs with differing desired releasekinetics. For example, making more side chains along the polymer thatare hydrophilic will generally make the polymer more hydrophilic overalland will also generally increase the release rate of an agent from thepolymer.

In certain embodiments, the polymeric particles or films delay releaseof chemotherapeutic agents. The delayed release can coincide with woundhealing. In certain embodiments, drug delivery is delayed for a periodof approximately 0-6 weeks. In other embodiments, the drug is releasedover a period of 1-6 weeks. In another embodiment, the drug is releasedover a period of 2 weeks. In other embodiments, the drug is released forup to 3 months. One method of controlling the rate of release from theparticles is by varying the ratio of different monomer units duringpolymerization. For example, a ratio of 20:80 of glycerol and caproicacid provides polymers and resulting microparticles that release drugover five days.

Provided herein are particles, including microparticles andnanoparticles. In certain embodiments, the size of the polymer particlesdescribed herein are between 2 and 100 nm in diameter. In otherembodiments, the size of the polymer particles are between 0.02-10micrometers in diameter. In other embodiments, the size of the polymerparticles are between 1-50 micrometers in diameter. Other polymericparticles of a larger size can be useful at specific sites, such aswhere tumor regrowth is prevalent. For example, polymeric particles of alarger size can be useful at a surgical margin, where suturing orstapling has occurred, or within a naïve or treated tumor such as anablated cavity secondary to radiofrequency ablation or other therapy, orwithin a spontaneous cavity such as occurs in squamous cell carcinoma.Placement of polymeric particles within other spontaneous cavities couldbe utilized to result in sclerosis of the cavity, either with release ofspecific sclerosing agents such as talc powder, alcohol or doxycyclin asexamples or other inflammatory agents. This approach can then beutilized in the treatment of bullous disease in emphysema or infectiousdiseases such as ecchinococcal cysts, for example.

The new monomers and polymers can also be used to prepare biodegradableoligomers, polymers, macromolecules, and copolymers using standardtechniques. The oligomers, polymers, macromolecules and copolymers cancontain alkyl side chains formed between [1] a monomer or macromolecularunit containing at least one functional side group; [2] alkyl chainscontaining 1-50 carbon units; and, in certain embodiments, [3] astructurally different monomer or macromolecular unit. In certainembodiments, the macromolecular materials can be elastic solids orviscoelastic solids. In various embodiments, the macromolecularmaterials provided herein are hydrophobic or hydrophilic. In otherembodiments, a macromolecular material provided herein undergoes achange from hydrophobic to hydrophilic in response to a change in pH. Incertain embodiments, the macromolecular materials provided herein swellto a size that destabilizes or destroys a cell or cellular compartment.

EXAMPLES

The invention is further described in the following examples, which donot limit the scope of the invention described in the claims.

Example 1 Synthesis of5-Methyl-2-(2,4,6-trimethoxyphenyl)-[1,3]-5-dioxan-5-yl-methylmethacrylate

5-Methyl-2-(2,4,6-trimethoxyphenyl)-[1,3]-5-dioxan-5-yl-methanol wasprepared according a modification of a previously reported method(Gillies et al., J Am Chem Soc 126:11936-43, 2004). First,1,1,1-tris(hydroxymethyl)ethane and 2,4,6-trimethoxybenzaldehyde weredissolved in tetrahydrofuran, and 5 Å molecular sieves were added as adesiccant. A catalytic amount of p-toluenesulfonic acid was then addedto the mixture, and the reaction was allowed to proceed at roomtemperature. When the reaction was complete, triethylamine was added toquench the acid. The molecular sieves were then removed usingfiltration. The solvent was removed via rotary evaporation under reducedpressure, and the residue dissolved in dichloromethane. This mixture wasthen washed three times with 100 mM pH 8.0 phosphate buffer and driedover anhydrous sodium sulfate. The solvent was subsequently removedusing rotary evaporation under reduced pressure, and the residue waspurified using silica gel chromatography.

5-Methyl-2-(2,4,6-trimethoxyphenyl)-[1,3]-5-diox-anylmethanol andtriethylamine were dissolved in dichloromethane and chilled to 0° C.Methacryloyl chloride was then added drop wise to the mixture. Aftermixing for 16 h, the mixture was then washed three times with 100 mM pH8.0 phosphate buffer and dried over anhydrous sodium sulfate. Thesolvent was subsequently removed using rotary evaporation under reducedpressure, and the residue, and the title compound was isolated usingsilica gel chromatography.

Example 2 Synthesis of 5-Methyl-2-phenyl-[1,3]-5-dioxanylmethanol

1,1,1-Tris(hydroxymethyl)ethane (2.61 g, 21.7 mmol) andp-toluenesulfonic acid (0.339 g, 1.97 mmol) were dissolved inbenzaldehyde (2.8 mL, 2.9 g, 28 mmol) and stirred at 45° C. for 1 h. Atthis time, toluene (1.0 mL) was added to the solution, and toluene/waterwas distilled out of the mixture at 95° C. Fresh toluene was added, anddistillation was carried out again. This process was repeated until nowater was observed in the distillate. Sodium bicarbonate was added toquench the acid, and excess sodium bicarbonate was removed usingfiltration. The remaining toluene was removed via rotary evaporation,leaving a slightly yellow oil. This mixture was then separated usingsilica gel chromatography. The product was obtained as a white solid at41.8% yield.

Example 3 Synthesis of 5-Methyl-2-phenyl-[1,3]-5-dioxanylmethylMethacrylate

5-Methyl-2-phenyl-[1,3]-5-dioxanylmethanol (0.504 g, 2.42 mmol) andtriethylamine (0.68 mL, 0.49 g, 4.8 mmol) were dissolved indichloromethane and chilled to 0° C. Methacryloyl chloride (0.35 mL,0.37 g, 3.6 mmol) was then added drop wise to the mixture. After mixingfor 16 hours, the mixture was then washed 100 mM pH 8.0 phosphate buffer(50 mL×3) and dried over anhydrous sodium sulfate. The solvent wassubsequently removed using rotary evaporation under reduced pressure,and the product was isolated using silica gel chromatography at 83.9%yield.

Example 4 Synthesis of 1,3-bis(benzyloxy)propan-2-yl Methacrylate

1,3-bis(benzyloxy)propan-2-ol (0.45 mL, 0.50 g, 1.8 mmol) andtriethylamine (0.52 mL, 0.37 g, 3.7 mmol) were dissolved indichloromethane and chilled to 0° C. Methacryloyl chloride (0.27 mL,0.29 g, 2.8 mmol) was then added drop wise to the mixture. After mixingfor 16 h, the mixture was then washed 100 mM pH 8.0 phosphate buffer (50mL×3) and dried over anhydrous sodium sulfate. The solvent wassubsequently removed using rotary evaporation under reduced pressure,and the product was isolated using silica gel chromatography at 81.0%yield.

Example 5 Poly(benzyloxy glycerol carbonate-co-ε-caprolactone)

5-(benzyloxymethyl)-1,3-dioxan-2-one (624 mg, 3 mmol) and ε-caprolactonewere combined of varying ratios (to a total of 10.0 mmol) in a 10 mLschlenk flask and subsequently evacuated and flushed with N₂ threetimes. Meanwhile, the catalyst (Sn(oct)₂, 6.5 μL, 0.02 mmol,monomer/initiator ratio=500) was evacuated in a small flask for 60minutes. The Schlenk flask was partially submerged in a thermostattedoil bath, preheated to 140° C. Toluene (400 μL) was added to thecatalyst and the mixture was injected via syringe to the monomers. Thereaction was stirred for 48 hours, removed from heat, and cooled to roomtemperature. The polymer was dissolved in dichloromethane (10 mL) andprecipitated in cold methanol. The solvent was decanted and subsequentlydried by evaporation. The resulting polymer formed either a viscous oilor white solid precipitate depending on the carbonate content of thecopolymer. Copolymers were formed with the following carbonate molefractions: 0.05, 0.10, 0.20, 0.30, 0.40, 0.50, 1.00.

Example 6 Poly(hydroxy glycerol carbonate-co-ε-caprolactone)

Poly(benzyloxy glycerol carbonate-co-ε-caprolactone) (1.0 g, 2.02 mmol)was dissolved in 50 mL dry dichloromethane inside a Parr bottle. 10%Pd/C (50 mg) and 20% Pd(OH)₂/C (50 mg) were then added to the solution.The reaction mixture was evacuated and purged with hydrogen three times.The flask was then pressurized to 60 psi with hydrogen and shaken for 24hours. The reaction mixture was filtered through Celite and the filtercake washed with 50 mL dichloromethane. The solvents were thenevaporated to yield the final polymer. The resulting polymer formedeither a viscous oil or white solid precipitate depending on thecarbonate content of the copolymer. Copolymers were formed with thefollowing carbonate mole fractions: 0.05, 0.10, 0.20, 0.30, 0.40, 0.50,1.00.

Table 1 below indicates the composition, molecular weight, and thermaldata of the different copolymers, which are illustrated by structuralformulas below the table. In Table 1, CL=caprolactone; CG carbonate ofglycerol f_(cg)=mole percent carbonate monomer in polymerization feed;F_(cg)=mole percent carbonate monomer in copolymer; M_(n)=number averagemolecular weight; PDI=polydispersity index; T_(g)=glass transitiontemperature; T_(c)=crystallization temperature; T_(m)=meltingtemperature; H_(f)=heat of fusion. TABLE 1 Molecular Weights ThermalProperties M_(n) M_(n) M_(w)/ T_(g) T_(c) T_(m) ΔH_(f) Polymer f_(cg)F_(cg) (theo.) (SEC) M_(n) (° C.) (° C.) (° C.) (J/g) CL-CG-100-0 0 057,000 22,700 1.47 −64 36 57 61.5 CL-CG-90-10-Bn 10 11 61,700 13,3001.67 −54 8 40 38.5 CL-CG-90-10-OH 10 11 57,200 12,200 1.67 −59 7 35 32.6CL-CG-80-20-Bn 20 23 66,400 10,200 1.96 −49 −4 31 25.4 CL-CG-80-20-OH 2023 57,400 8,600 1.96 −56 0 23 8.5 CL-CG-80-20-C6-OH 20 23 68,800 10,1001.91 −47 −1 43 33 CL-CG-80-20-C5-COOH 20 23 70,200 10,400 1.96 −46 −5 4033 CL-CG-80-20-C6-NH₂ 20 23 68,700 10,100 1.94 −44 8 44 35CL-CG-70-30-Bn 30 30 71,100 9,300 1.78 −43 3 22 13.4 CL-CG-60-40-Bn 4042 75,800 7,900 1.94 −38 none none none CL-CG-0-100-Bn 100 100 104,0003,600 3.16 −10 none none none

CL-CG-100-0

CL-CG-90-10-Bn

CL-CG-90-10-OH

CL-CG-80-20-Bn

CL-CG-80-20-OH

CL-CG-80-20-C6-OH

CL-CG-80-20-C5-COOH

CL-CG-80-20-C6-NH2

CL-CG-70-30-Bn

CL-CG-60-40-Bn

CL-CG-0-100-Bn

Example 7 Poly(myristic acid carbonate-co-ε-caprolactone)

Poly(benzyloxy glycerol carbonate-co-ε-caprolactone) (1.0 g, 2.02 mmol),myristic acid (0.690 g, 3.03 mmol) and dimethylaminopyridine (DMAP)(0.123 g, 1.01 mmol) were dissolved in 100 mL dry dichloromethane.Dicyclohexylcarbodiimide (DCC) (0.500 g, 2.42 mmol) was added to thereaction mixture and a white precipitate formed. The mixture was stirredfor 24 hours at room temperature under nitrogen. The precipitatecompound was isolated by filtration and the filtrate was concentrated.The concentrated filtrate was dissolved in dichloromethane andprecipitated in cold methanol (25 mL). The solvent was decanted andsubsequently dried by evaporation. The resulting polymer was a whitesolid precipitate.

Example 8 Poly(stearic acid carbonate-co-ε-caprolactone)

Poly(benzyloxy glycerol carbonate-co-ε-caprolactone) (1.0 g, 2.02 mmol),stearic acid (0.859 g, 3.03 mmol) and DMAP (0.123 g, 1.01 mmol) weredissolved in 100 mL dry dichloromethane. DCC (0.500 g, 2.42 mmol) wasadded to the reaction mixture and a white precipitate formed. Themixture was stirred for 24 hours at room temperature under nitrogen. Theprecipitate compound was isolated by filtration and the filtrate wasconcentrated. The concentrated filtrate was dissolved in dichloromethaneand precipitated in cold methanol (25 mL). The solvent was decanted andsubsequently dried by evaporation. The resulting polymer was a whitesolid precipitate.

Example 9 Poly(oleic acid carbonate-co-ε-caprolactone)

Poly(benzyloxy glycerol carbonate-co-ε-caprolactone) (250 mg, 0.43 mmol)was dissolved in 25 mL of pyridine and cooled to 0° C. Oleoyl chloride(183 mg, 0.65 mmol) was added drop by drop. The mixture was stirred for24 hours at room temperature under nitrogen. The pyridine was removedunder vacuum, the crude product was dissolved in dichloromethane, andprecipitated in cold methanol (25 mL). The solvent was decanted andsubsequently dried by evaporation. The resulting polymer was a whitesolid precipitate.

Example 10 Amine Functionalized Poly Carbonate ofGlycerol-co-caprolactone

An amine-derivitized copolymer poly(6-amino-hexanoic acid2-oxo-1,3-dioxan-5-yl ester-co-ε-caprolactone) was prepared using thefollowing methods.

Synthesis of poly(fmoc-6-amino-hexanoic acid 2-oxo-1,3-dioxan-5-ylester-co-ε-caprolactone)

Fmoc-6-amino-hexanoic acid (0.277 g, 0.78 mol),poly(5-hydroxy-1,3-dioxan-2-one-co-ε-caprolactone) (1.5 g, 2.6 mmol, 22mol % carbonate), DCC (0.129 g, 0.63 mmol), and DMAP (0.032 g, 0.26mmol) were dissolved in DCM (20 mL). The solution was stirred at RT for18 h. The DCU was filtered and the solvent evaporated. The product wasdissolved in dichloromethane (10 mL) and precipitated in cold methanol.The solvent was decanted and subsequently dried by evaporation (85%yield). Addition of the amine side chain was determined by the presenceof the methylene group nearest the Fmoc protecting group, as well as theFmoc protecting group itself, with peaks in the ¹H NMR spectrum at3.10-3.19 (m, 2H, OCH₂), and 4.45 (s, 2H, PhCH₂), 7.24-7.38 (m, 5H,aromatic), respectively.

Deprotection of poly(fmoc-6-Amino-hexanoic acid 2-oxo-1,3-dioxan-5-ylester-co-ε-caprolactone)

The copolymer (300 mg) was dissolved in a 40% mixture of piperidine (16mL) and dry dimethyl formamide (24 mL) and the reaction was stirred for90 min. The solvents were evaporated under reduced pressure. The productwas dissolved in dichloromethane (10 mL) and precipitated in coldmethanol. The solvent was decanted and subsequently dried by evaporation(quantitative yield). Complete deprotection was determined by theabsence of the Fmoc protecting group peaks in the ¹H NMR spectrum at4.88-4.95 (m, 2H, CH₂), and 7.24-7.75 (m, 5H, aromatic).

Example 11 Hydroxyl Functionalized Poly Carbonate ofGlycerol-co-caprolactone

A primary alcohol-derivitized copolymer poly(6-hydroxy-hexanoic acid2-oxo-1,3-dioxan-5-yl ester-co-ε-caprolactone) was synthesized using thefollowing steps.

Synthesis of 6-benzyloxy-hexanoic acid

ε-caprolactone (10 mL, 0.18 mol), benzyl bromide (13.4 mL, 0.11 mol),and potassium hydroxide (11.3 g, 0.281 mol) were dissolved in toluene(200 mL). The reaction flask was placed in a 120° C. pre-heated oil bathand refluxed overnight under stirring. The mixture was then neutralizedusing 1 M HCl (300 mL), the toluene evaporated off, and the productextracted using dichloromethane (3×300 mL) to afford a mixture of monoand di-protected 6-hydroxy-hexanoic acid. The crude product wassaponificated with 1M sodium hydroxide (200 mL) and methanol (200 mL),extracted with dichloromethane (3×200 mL), and the solvent wasevaporated under reduced pressure to afford pure 6-benzyloxy-hexanoicacid (72% yield). ¹H NMR (CDCl₃) 1.38-1.46 (m, 2H, CH₂), 1.57-1.68 (m,4H, CH₂CH₂), 2.32-2.38 (m, 2H, CH₂COOH), 3.42-3.46 (m, 2H, OCH₂),4.48-4.53 (s, 2H, PhCH₂), 7.27-7.31 (m, 5H, aromatic).

Poly(6-benzyloxy-hexanoic acid 2-oxo-1,3-dioxan-5-ylester-co-ε-caprolactone)

6-Benzyloxy-hexanoic acid (0.173 g, 0.78 mmol),poly(5-hydroxy-1,3-dioxan-2-one-co-ε-caprolactone) (1.5 g, 2.6 mmol, 22mol % carbonate), DCC (0.129 g, 0.63 mmol), and DMAP (0.032 g, 0.26mmol) were dissolved in DCM (20 mL). The solution was stirred at RT for18 h. The DCU was filtered and the solvent evaporated. The product wasdissolved in dichloromethane (10 mL) and precipitated in cold methanol.The solvent was decanted and subsequently dried by evaporation (86%yield). Addition of the alcohol side chain was determined by thepresence of the methylene group nearest the benzyl protecting group, aswell as the benzyl protecting group itself, with peaks in the ¹H NMRspectrum at 3.40-3.44 (m, 2H, OCH₂), and 4.48-4.53 (s, 2H, PhCH₂),7.27-7.31 (m, 5H, aromatic), respectively.

Deprotection of poly(6-benzyloxy-hexanoic acid 2-oxo-1,3-dioxan-5-ylester-co-ε-caprolactone)

The copolymer (300 mg) was dissolved in 50 mL dry dichloromethane insidea Parr bottle. 10% Pd/C (50 mg) and 20% Pd(OH)₂/C (50 mg) were thenadded to the solution. The reaction mixture was evacuated and purgedwith hydrogen three times. The flask was then pressurized to 60 psi withhydrogen and shaken for 24 hours. The reaction mixture was filteredthrough Celite and the filter cake washed with 50 mL dichloromethane.The solvents were then evaporated to yield the final polymer(quantitative yield). Complete deprotection was determined by theabsence of the benzyl protecting group peaks in the ¹H NMR spectrum at4.48-4.53 (s, 2H, PhCH₂), 7.27-7.31 (m, 5H, aromatic).

Example 12 Carboxylic Acid Functionalized Poly Carbonate ofGlycerol-co-caprolactone

A carboxylic acid-derivitized copolymer poly(hexanedioic acidmono-(2-oxo-1,3-dioxan-5-yl) ester-co-ε-caprolactone) was synthesizedusing the following steps.

Synthesis of Hexanedioic Acid Monobenzyl Ester

DOWEX® 50W-X2 (2 g), benzyl formate (10 mL, mol), and adipic acid (2 g,mol) were added to octane (10 mL). The mixture was refluxed for 4 hoursat 100° C., and the crude product was purified via silica chromatographyto yield a clear, colorless liquid (87% yield). ¹H NMR (CDCl₃) 1.59-1.78(m, 4H, CH₂CH₂), 2.33-2.39 (m, 4H, CH₂COOH), 5.09 (s, 2H, PhCH₂),7.25-7.30 (m, 5H, aromatic).

Poly(hexanedioic acidmono-(2-oxo-1,3-dioxan-5-yl)ester-co-ε-caprolactone)

Hexanedioic acid monobenzyl ester (0.184 g, 0.78 mmol),poly(5-hydroxy-1,3-dioxan-2-one-co-ε-caprolactone) (1.5 g, 2.6 mmol, 22mol % carbonate), DCC (0.129 g, 0.63 mmol), and DMAP (0.032 g, 0.26mmol) were dissolved in dichloromethane (20 mL). The solution wasstirred at RT for 18 h. The DCU was filtered and the solvent evaporated.The product was dissolved in dichloromethane (10 mL) and precipitated incold methanol. The solvent was decanted and subsequently dried byevaporation (83% yield). Addition of the carboxylic acid side chain wasdetermined by the presence of the benzyl protecting group, with peaks inthe ¹H NMR spectrum at 5.06 (s, 2H, PhCH₂), 7.27-7.33 (m, 5H, aromatic).

Deprotection of poly(6-benzyloxy-hexanoic acid 2-oxo-1,3-dioxan-5-ylester-co-ε-caprolactone)

The copolymer (300 mg) was dissolved in 50 mL dry dichloromethane insidea Parr bottle. 10% Pd/C (50 mg) and 20% Pd(OH)₂/C (50 mg) were thenadded to the solution. The reaction mixture was evacuated and purgedwith hydrogen three times. The flask was then pressurized to 60 psi withhydrogen and shaken for 24 hours. The reaction mixture was filteredthrough Celite and the filter cake washed with 50 mL dichloromethane.The solvents were then evaporated to yield the final polymer(quantitative yield). Complete deprotection was determined by theabsence of the benzyl protecting group peaks in the ¹H NMR spectrum at5.06 (s, 2H, PhCH₂), 7.27-7.33 (m, 5H, aromatic).

Example 13 Poly(benzyloxy glycerol thiol carbonate-co-ε-caprolactone)

5-(benzyloxymethyl)-1,3-dithian-2-one and ε-capro-thiollactone arecombined with varying ratios (to a total of 10.0 mmol) in a 10 mLschlenk flask and subsequently evacuated and flushed with N₂ threetimes. Meanwhile, the catalyst (Sn(oct)₂, 6.5 μL, 0.02 mmol,monomer/initiator ratio=500) is evacuated in a small flask for 60minutes. The Schlenk flask is partially submerged in a thermostatted oilbath, preheated to 140° C. Toluene (400 μL) is added to the catalyst andthe mixture injected via syringe to the monomers. The reaction isstirred for 48 hours, removed from heat, and cooled to room temperature.The polymer is dissolved in dichloromethane (10 mL) and precipitated incold methanol. The solvent is decanted and subsequently dried byevaporation. The resulting polymer forms either a viscous oil or whitesolid precipitate depending on the carbonate content of the copolymer.

Example 14 Poly(hydroxy glycerol thiol carbonate-co-ε-caprolactone)

Poly(benzyloxy glycerol thiol carbonate-co-ε-caprolactone) is dissolvedin 50 mL dry dichloromethane inside a Parr bottle. 10% Pd/C (50 mg) and20% Pd(OH)₂/C (50 mg) are added to the solution. The reaction mixture isevacuated and purged with hydrogen three times. The flask is pressurizedto 60 psi with hydrogen and shaken for 24 hours. The reaction mixture isfiltered through Celite and the filter cake washed with 50 mL ofdichloromethane. The solvents are evaporated to yield the final polymer.

Example 15 Poly(stearic acid thiol carbonate-co-ε-caprolactone)

Poly(benzyloxy glycerol thiol carbonate-co-ε-caprolactone), stearicacid, and DMAP are dissolved in 100 mL dry dichloromethane. DCC is addedto the reaction mixture and a white precipitate forms. The mixture isstirred for 24 hours at room temperature under nitrogen. The precipitatecompound is isolated by filtration and the filtrate was concentrated.The concentrated filtrate is dissolved in dichloromethane andprecipitated in cold methanol (25 mL). The solvent is decanted andsubsequently dried by evaporation.

Example 16 Fabrication of Paclitaxel Containing PLGA Microparticles

Bioabsorbable poly D,L-lactide-co-glycolide (PLGA) microparticles can beused for the delivery of paclitaxel. The fabrication techniques used tocreate PLGA microparticles were modified from Edlund & Albertsson andWang et. al. (Edlund et al., Adv. Polymer Sci., 157:67-112, 2001; Wanget al., Chem. Pharm. Bull., (Tokyo) 44:1935, 1996) and utilized a waterin oil emulsion technique. First, 0.5 g of 75:25 PLGA (AbsorbablePolymer International, Birmingham, Ala.) tablets (the greater the ratioof lactic acid to glycolic acid the slower the release) were dissolvedin 4 mL dichloromethane (Sigma Aldrich, St. Louis, Mo.) using avortexing device. After the plastic was completely dissolved, 50 mg ofpaclitaxel (Taxol, MP Biomedical Irvine, Calif.) previously solubilizedin 100 μl of dimethyl sulfoxide (DMSO, Fisher Hampton, N.H.), was addedand further vortexed. In the fabrication of control PLGA beads only DMSOwas added. The solution was placed in 10 ml of 5% polyvinyl alcoholsurfactant (Fisher) and vortexed for 15 minutes (or sonicated using aprobe tip sonicator) and stirred overnight. The microparticles werecollected and washed three times in 50 mL of distilled/deionized water.Following washing, the microparticles were lyophilized (freeze dried)and stored at −20° C. to insure the stability of Paclitaxel. Theencapsulation efficiency of taxol by the microparticles was determinedto be 74%+/−4% by HPLC analysis.

Example 17 Synthesis of Nanoparticles by Miniemulsion

Nanoparticles were prepared using a modification of a miniemulsionpolymerization method previously reported (Landfester et al.,Macromolecules 32:5222-8, 1999). Briefly,5-methyl-2-(2,4,6-trimethoxyphenyl)-[1,3]-5-diox-anylmethyl methacrylateand 2,2′-azobis(2-methylpropionitrile) (AIBN), a free-radical initiator,were dissolved in dichloromethane, followed by removal of the solventvia rotary evaporation until a viscous mixture remained. Alternatively,5-methyl-2-(2,4,6-trimethoxyphenyl)-[1,3]-5-diox-anylmethylmethacrylate, 0.25 mg of paclitaxel, and2,2′-azobis(2-methylpropionitrile) (AIBN), a free-radical initiator,were dissolved in dichloromethane, followed by removal of the solventvia rotary evaporation until a viscous mixture remained. This viscousmixture was then mixed with a solution of sodium dodecyl sulfate, astabilizing surfactant, in 10 mM pH 8 phosphate buffer. This mixture wasthen sonicated for 1 hour (1 second pulses with a 2 second delay) with30 W of power, forming the miniemulsion and allowing the solvent toevaporate. Following sonication, the miniemulsion was transferred onto atemperature-controlled oil bath and stirred at 65° C. for 2 hours toinitiate the free-radical polymerization. The resulting polymericnanoparticles were then dialyzed against 5 mM pH 8 phosphate buffer overtwo days to remove excess surfactant and salts.

Example 18 Synthesis of Nanoparticles Using Photoinitiation

5-Methyl-2-(2,4,6-trimethoxyphenyl)-[1,3]-5-dioxan-5-yl-methylmethacrylate was dissolved in dichloromethane, followed by removal ofthe solvent via rotary evaporation until a viscous mixture remained.Alternatively, methyl-2-phenyl-[1,3]-5-dioxanylmethyl methacrylate and0.25 mg of paclitaxel was dissolved in dichloromethane, followed byremoval of the solvent via rotary evaporation until a viscous mixtureremained. This viscous oil was then mixed with a solution of sodiumdodecyl sulfate, the stabilizing surfactant, in 20 mM triethanolaminebuffer. This mixture was then sonicated for 30 min (1 s pulses with a 2s delay) with 30 W of power, forming the miniemulsion and allowing thesolvent to partially evaporate. Following sonication, Eosin Y and1-vinyl-2-pyrrolidone were added to the emulsion to give finalconcentrations of 0.2 mM and 2 mM, respectively. This mixture was thenexposed to light from a mercury arc lamp operating at 300 W for 10 minwhile being stirred vigorously, causing polymerization. Followingphotopolymerization, the particles were stirred overnight while open tothe air to allow any remaining solvent to evaporate. The resultingpolymeric nanoparticles were then dialyzed against 5 mM pH 8 phosphatebuffer over two days to remove excess surfactant and salts.

Example 19 Nanoparticles Prepared by a Precipitation Method

5-Methyl-2-(2,4,6-trimethoxyphenyl)-[1,3]-5-dioxanylmethyl methacrylate(0.45 g, 1.2 mmol) and benzoyl peroxide (2.6 mg, 0.011 mmol) weredissolved in dry toluene (10 mL). The flask was evacuated and refilledwith nitrogen three times to remove oxygen. The mixture was then stirredat 70° C. for 14 hours. The solvent was removed by rotary evaporation,and the remaining material was dissolved in CH₂Cl₂ (5 mL) andprecipitated in cold diethyl ether (50 mL). The solid precipitate wascollected by vacuum filtration. The product was obtained as a whitepowder at 36.5% yield.

Nanoparticles were prepared by first dissolving the polymer (50 mg) inCH₂Cl₂ (1.0 mL) and dissolving sodium dodecyl sulfate (50 mg) indeionized water (10 mL). Alternatively, nanoparticles were prepared byfirst dissolving the polymer (50 mg) and paclitaxel (0.5 mg) in CH₂Cl₂(1.0 mL) and dissolving sodium dodecyl sulfate (50 mg) in deionizedwater (10 mL). The organic solution was then added to the aqueoussurfactant solution, and this mixture was sonicated at 30 W of power for5 minutes to produce the emulsion. The mixture was stirred while open tothe atmosphere overnight to evaporate the excess CH₂Cl₂. Dialysis usinga membrane with a 3400 molecular weight cutoff was used to remove excesssurfactant. Nanoparticles prepared using this monomer do not swell atpH>1.

Example 20 Fabrication of Poly(hydroxy glycerolcarbonate-co-ε-caprolactone) Drug-eluting Microparticles

Poly(hydroxy glycerol carbonate-co-ε-caprolactone) microparticles wereused for the delivery of pemetrexed. The fabrication techniques used tocreate the microparticles utilize a water in oil in water emulsiontechnique. First, 0.5 g of 20:80 poly(hydroxy glycerolcarbonate-co-ε-caprolactone) was dissolved in 4 mL dichloromethane(Sigma Aldrich, St. Louis, Mo.) using a vortexing device. After thepolymer was completely dissolved, 50 mg of pemetrexed previouslysolubilized in 0.9% NaCl, was added and further vortexed. In thefabrication of control poly(hydroxy glycerolcarbonate-co-ε-caprolactone) beads only 0.9% NaCl was added. Thesolution was placed in 10 ml of 5% poly vinyl alcohol surfactant(Fisher) and vortexed for 15 minutes (or sonicated using a probe tipsonicator) and stirred overnight. The microparticles were collected andwashed three times in 50 ml of distilled/deionized water. Followingwashing, the microparticles were lyophilized (freeze dried) and storedat −20° C. to insure the stability of pemetrexed.

Example 21 Fabrication of Poly(hydroxy glycerolcarbonate-co-ε-caprolactone) Nanoparticles with Fluorescent Tag

7-(diethylamino)coumarin-3-carboxylic acid (0.005 g, 19.5 nmol),poly(5-hydroxy-1,3-dioxan-2-one-co-ε-caprolactone) (1.5 g, 2.6 mmol, 22mol % carbonate), DCC (0.129 g, 0.63 mmol), and DMAP (0.032 g, 0.26mmol) were dissolved in DCM (20 mL). The solution was stirred at RT for18 hours. The DCU was filtered and the solvent evaporated (quantitativeyield). The crude product was redissolved in THF, purified usingSephadex LH-20 chromatography and further dialyzed (Pierce, 3,500 MWCO)for approximately 48 hours to ensure all residual unbound dye wasremoved.

Coumarin-bound copolymer particles were prepared by an emulsion/solventevaporation method. Briefly, 1.0 g of copolymer was dissolved in 20 mLdichloromethane. The solution was poured into a mixture of 200 mLdeionized water containing 0.5% w/v SDS. The emulsion was stirred for 5minutes before being sonicated (˜30 W) for 30 minutes, and finallydialyzed for approximately 48 hours to remove the SDS.

The nanoparticle stock solution (5 mg/mL) was diluted to a finalconcentration of 0.01 mg/mL with serum-free medium (Dulbecco's ModifiedEagle Medium). A549 human lung carcinoma cells (American Type CultureCollection, Manassas, Va.) were plated onto a 96 well plate at a densityof 5,000 cells/well and incubated overnight, or until about 90%confluence. The medium from each well was removed and replaced with 100μL of 0.01 mg/mL nanoparticle solution and the cells were subsequentlyincubated with the particles for 2 hours. The nanoparticle suspensionwas then removed, the cells were washed directly three times with PBS,and the cells were imaged immediately via fluorescence microscopy with aFITC filter.

Example 22 Fabrication of Poly(stearic acid carbonate-co-ε-caprolactone)Nanoparticles

The nanoparticles were prepared by an emulsion/solvent evaporationmethod. Briefly, poly(stearic acid carbonate-co-ε-caprolactone) wasdissolved in 20 mL dichloromethane. Alternatively, poly(stearic acidcarbonate-co-ε-caprolactone) was dissolved in 20 mL dichloromethanecontaining either 1 or 10 wt % paclitaxel per weight of polymer. Thesolution was poured into a mixture of 200 mL deionized water containing0.5% w/v SDS. The emulsion was stirred for 5 minutes before beingsonicated (30 W) for 30 minutes, and finally dialyzed for approximately1 hour to remove the SDS.

Example 23 Nanoparticle Expanding In Acidic But Not Neutral Conditions

A sample of the nanoparticles from Example 18 was diluted in buffer at apH 4, 5, or 7.4 and maintained at 37° C. The diameter of the particleswas then measured at regular time intervals using dynamic lightscattering (DLS), showing how the particles increased in size over time.Prior to each DLS measurement, the samples were sonicated for 5 secondsto break up aggregates. Particle swelling from 100 nm in diameter tonear 1 μm in diameter was observed (see FIG. 9). In addition, therelease of free 2,4,6-trimethoxybenzaldehyde was observed using UV/V isspectroscopy at a wavelength of 292 nm, also indicating deprotection ofthe polymer side groups (see FIG. 10).

These particles are useful for controlled release applications as wellas for cosmetic applications in which the increase in volume couldreduce wrinkles of increase the sized of tissue into which thesepolymers are injected.

Example 24 Nanoparticle and Swelling from A Sugar Analog

Synthesis of1,2:5,6-di-O-isopropylidene-3-O-methacryloyl-α-D-glucofuranose: Thesynthesis of this compound was carried out as described by Black et al.and is described briefly. (Black et al., Journal of the ChemicalSociety, 4433-4439, 1963). 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose(1.00 g, 3.86 mmol) and methacrylic anhydride (1.2 mL, 1.2 g, 8.1 mmol)were dissolved in pyridine (5 mL) and stirred at 65° C. for 3.5 hours.Then water (2.5 mL) was added, and stirring at 65° C. was continued foranother 1.5 hours and then at room temperature overnight. The mixturewas extracted with hexanes (5 mL×3), and the combined hexanes extractswere then washed with 1 M NaOH (15 mL×3) and deionized water (15 mL),followed by drying over Na₂SO₄. The solvent was removed using rotaryevaporation, and the remaining compound was dried under high vacuum. Theproduct was obtained as a clear oil at 74.2% yield.

Nanoparticles were prepared from the resulting product by methodsdescribed herein. A sample of the nanoparticles was diluted in 0.1 M HCland maintained at 25° C. The diameter of the particles was then measuredat regular time intervals using dynamic light scattering (DLS), showinghow the particles increased in size over time (FIG. 12). FIG. 12 showsthat at a pH of about 1.0, the particle size changes from about 200 nmto about 1600 nm over the course of about 24 hours, whereas at a pH ofabout 3.0, the particle size is stable over the same time period.

Example 25 Formation of Single-layer Polymer Films

Polymer films were cast onto glass by depositing a polymer solutioncomprised of an individual copolymer including but not limited topoly(stearic acid carbonate-co-ε-caprolactone), dissolved indichloromethane, tetrahydrofuran, or toluene, using a microsyringe. Thesolvent was removed by slow evaporation overnight and then placed underreduced pressure for 24 hours.

Example 26 Formation of Multi-layered Polymer Films

Poly(stearic acid carbonate-co-ε-caprolactone) films were adheredbetween poly(lactic-co-glycolic acid) films. A poly(lactic-co-glycolicacid)/dichloromethane solution was deposited onto glass using amicrosyringe to form a film. A poly(stearic acidcarbonate-co-ε-caprolactone)/dichloromethane solution was deposited ontothe poly(lactic-co-glycolic acid) film using a microsyringe to form asecond layer. A poly(lactic-co-glycolic acid)/dichloromethane solutionwas deposited onto the poly poly(stearic acidcarbonate-co-ε-caprolactone) film using a microsyringe to form a thirdlayer.

Example 27 Deposition of Polymer Films on a Substrate

Polymer films were cast onto substrates composed of either glass,collagen, pericardium, TEFLON®, or titanium by depositing a polymersolution comprised of an individual copolymer including but not limitedto poly(stearic acid carbonate-co-ε-caprolactone), dissolved indichloromethane, tetrahydrofuran, or toluene, using a microsyringe. Thesolvent was removed by slow evaporation overnight and then placed underreduced pressure for 24 hours.

Example 28 Incorporation 10-hydroxycaptothecin into Polymer Films

Drug loaded polymeric films were cast or sprayed onto glass bydepositing a polymer solution of poly(stearic acidcarbonate-co-ε-caprolactone), dichloromethane, and10-hydroxycamptothecin, using a microsyringe or aerosol device. Thesolvent was removed by slow evaporation overnight and then placed underreduced pressure for 24 hours.

Example 29 Incorporation and Patterning of 10-Hydroxycaptothecin intoPolymer Films

Patterned drug loaded polymeric films were cast onto glass by using amicroprinter or microsyringe by depositing a polymer solution ofpoly(stearic acid carbonate-co-ε-caprolactone), dichloromethane, and10-hydroxycamptothecin, in a controlled manner to form patterns such asstripes and dots. The solvent was removed by slow evaporation overnightand then placed under reduced pressure for 24 hours. This method canalso be used with more than one polymer simultaneously.

Example 30 Release of 10-Hydroxycamptothecin from Poly(ε-caprolactone)

Drug-loaded polymer films were cast onto glass by depositing a polymersolution comprised of poly(caprolactone) (5 mg), dichloromethane (50μL), and 10-hydroxycamptothecin (100 μg), using a microsyringe. Thesolvent was removed by slow evaporation over night and then placed underreduced pressure for 24 hours. An initial burst was seen over the firsttwo days, releasing at a rate of about 5 μg/day.

Drug-loaded polymer films were also cast onto glass by depositing apolymer solution comprised of poly(stearic carbonate-co-ε-caprolactone)(5 mg), dichloromethane (50 μL), and paclitaxel (100 μg), using amicrosyringe. The solvent was removed by slow evaporation over night andthen placed under reduced pressure for 24 hours. The resulting filmswere homogenous and opaque, with good adherence to the glass substrate.The films released taxol over time.

Example 31 Release of 10-Hydroxycamptothecin or paclitaxel fromPoly(stearic acid carbonate-co-ε-caprolactone)

Drug-loaded polymer films were cast onto glass by depositing a polymersolution comprised of poly(stearic acid carbonate-co-ε-caprolactone) (5mg), dichloromethane (50 μL), and 10-hydroxycamptothecin (100 μg), usinga microsyringe. The solvent was removed by slow evaporation over nightand then placed under reduced pressure for 24 hours. A slight initialburst was seen over the first two days, releasing at a rate of about 3μg/day. Continuous release occurred over at least 30 days at a nearlyconstant rate of about 1 μg/day.

Alternatively, drug-loaded polymer films were cast onto glass bydepositing a polymer solution comprised of poly(steariccarbonate-co-ε-caprolactone) (5 mg), dichloromethane (50 μL), andpaclitaxel (100 μg), using a microsyringe. The solvent was removed byslow evaporation over night and then placed under reduced pressure for24 hours. The resulting films were homogenous and opaque, with goodadherence to the glass substrate. The films released taxol over time.

Example 32 Release of 10-Hydroxycamptothecin from Poly(hydroxy glycerolcarbonate-co-ε-caprolactone)

Drug-loaded polymer films were cast onto glass by depositing a polymersolution comprised of poly(hydroxy glycerol carbonate-co-ε-caprolactone)(5 mg), dichloromethane (50 μL), and 10-hydroxycamptothecin (100 μg),using a microsyringe. The solvent was removed by slow evaporation overnight and then placed under reduced pressure for 24 hours. An initialburst was seen over the first day, releasing at a rate of about 18μg/day. Continuous release occurred over at least 30 days, beginning ata rate of 3 μg/day and slowly decreasing to less than 1 μg/day at fourweeks.

Example 33 In Vitro Tumor Cytoxicity with Paclitaxel-Loaded Poly(stearicacid carbonate-co-ε-caprolactone) Nanoparticles

Lewis Lung Carcinoma (LLC) cells were washed with sterile phosphatebuffered saline (PBS) and trypsinized. The cells were then counted usinga Coulter counter and plated 3,000 cells/well in 96 well plates. Cellswere serum starved overnight and then treated with empty nanoparticles,paclitaxel-loaded nanoparticles (10% paclitaxel), and paclitaxel-loadednanoparticles (1% paclitaxel) for a five day period. A positive controlcontained 10% FBS or the same concentration of FBS provided for treatedcells, while a negative control lacked FBS. At the completion of theassay the cells were incubated with 50 μL of 1× Thiazolyl BlueTetrazolium Bromide (MTT, Sigma) dissolved in PBS at 37° C. for twohours. The media was then aspirated and 100 μL of DMSO was added to eachwell. The plates were then placed on a shaking device for 10 minutes andthe wells turned purple, corresponding with the numbers of viablemitochondria in the well. The plates were placed on an ELISA reader andscanned at a wavelength of 570 nm. The absorbance values were normalizedto values from a known number of stained cells. No cytotoxicity wasobserved with the empty nanoparticles (as a control, FIG. 3), whereascytotoxicity was observed with the taxol loaded nanoparticles, as shownin FIGS. 4 and 5.

Example 34 Release of 10-Hydroxycamptothecin from Poly((lauric myristic,palmitic, or stearic) glycerol carbonate-co-ε-caprolactone)

Drug-loaded polymer films were cast onto glass by depositing a polymersolution comprised of poly((lauric, myristic, palmitic, or stearic)carbonate-co-ε-caprolactone) (5 mg), dichloromethane (50 μL), and10-hydroxycamptothecin (100 μg), using a microsyringe. The solvent wasremoved by slow evaporation over night and then placed under reducedpressure for 24 hours. An initial burst was seen over the first day,releasing at a rate of about 8-10 μg/day. Continuous release occurredover at least 49 days, beginning at a rate of 1-3 μg/day and slowlydecreasing to less than 1 μg/day at four weeks (see FIG. 6). FIG. 6shows that increasing the hydrophobicity of the polymer decreasesrelease from the polymers. Intermediate release profiles to those showncan be obtained by mixing or blending the polymers.

Example 35 Release of 10-Hydroxycamptothecin from Poly(stearic glycerolcarbonate-co-ε-caprolactone) on Pericardium Strips

Drug-loaded polymer films were cast onto pericardium by depositing apolymer solution comprised of poly(stearic acidcarbonate-co-ε-caprolactone) (5 mg), dichloromethane (50 μL), and10-hydroxycamptothecin (100 μg), using a microsyringe. The solvent wasremoved by slow evaporation overnight and then placed under reducedpressure for 24 hours. An initial burst was seen over the first day,releasing at a rate of about 10 μg/day. Continuous release occurred overat least 40 days, beginning at a rate of 3 μg/day and slowly decreasingto less than 1 μg/day at four weeks (see FIG. 7).

Example 36 Cell Culture and Cell Proliferation Assays

Melanoma B16 (murine), Calu 6 (human lung carcinoma), A549 (human lungcarcinoma), and LLC (murine Lewis Lung Carcinoma) were incubated (37°C., 5% CO₂) with MEM (with 10% fetal bovine serum (FBS) and 1% essentialamino acids. The media was change once every three days. When notcultured, all cell lines were stored in RPMI freezing media at −80° C.(with 50% FBS, 40% RPMI and 10% dimethyl sulfoxide (DMSO)). Cell lineswere trypsinized from 15 cm plates and seeded into 96 well plates at aconcentration of 3000 cells per well. All cell lines were cultured for aperiod of at least three days before being tested in cell proliferationassays.

Tumor cells were washed with sterile phosphate buffered saline (PBS) andtrypsinized. The cells were then counted using a Coulter counter andplated 3,000 cells/well in 96 well plates. Cells were serum starvedovernight and then treated with paclitaxel, control microparticles, orpaclitaxel loaded microparticles the next day. A positive controlcontained 10% FBS or the same concentration of FBS provided for treatedcells, while a negative control lacked FBS. At the completion of theassay the cells were incubated with 50 μl of 1× Thiazolyl BlueTetrazolium Bromide (MTT, Sigma) dissolved in PBS at 37° C. for twohours. The media was then aspirated and 100 μl of DMSO was added to eachwell. The plates were then placed on a shaking device for 10 minutes andthe wells turned purple, corresponding with the numbers of viablemitochondria in the well. The plates were placed on an ELISA reader andscanned at a wavelength of 570 nm. The absorbance values were normalizedto values from a known number of stained cells. The dose of paclitaxelat which 50% of cells are killed, or LD50, was determined to be between1-10 ng/mL. Approximately 125,000 paclitaxel loaded microparticles/mLwere necessary to achieve similar paclitaxel concentrations and celldeath.

Example 37 Anti-Tumor Response In Vitro

Cell proliferation assays testing the effects of paclitaxel wereperformed using three tumor cell lines. Lewis Lung Carcinoma (LLC),Melanoma and Calu6 (human lung cancer) cell lines were plated at 3,000cells/well and when established, cultured in media with/withoutpaclitaxel. Some cultures were maintained with optimal growth factors(serum) whereas others were serum starved (non-growing) cultures. At theend of 5 days, tumor cell proliferation was assessed via MTT analysis.Data was plotted by normalization to the positive and negative controlcultures as 0% and 100% inhibition, respectively. The results indicatedthat media containing paclitaxel at a concentration of 1-10 ng/mLreliably inhibits growth of the LLC, melanoma, and Calu6 tumor celllines in proliferation assays. This data was obtained using mediacontaining 10% FBS (positive control).

Cell proliferation assays were utilized to study the effects ofpaclitaxel-loaded microparticles on tumor growth. Tumor cells wereplated at 3000 cells/well and positive (serum-rich) and negative(serum-poor) cultures were used to signify 0% and 100% growth inhibitionrespectively. It was found that the addition of 100,000-500,000microparticles/ml results in inhibition equal to paclitaxelconcentrations of 10 ng/mL despite the presence of serum rich media.Inhibition of tumor growth was not present with control (DMSO)microparticles that do not contain paclitaxel. These results demonstratethat paclitaxel-loaded microparticles are an effective means of drugdelivery and specifically result in an effective anti-tumor response invitro.

To determine the kinetics of the anti-tumor response elicited bypaclitaxel-loaded microparticles and to assess for a potential “bursteffect” of drug release, a cell proliferation assay comparingpaclitaxel-loaded microparticles and DMSO (control) microparticles usingthe melanoma cell line was run for five consecutive days with a plateundergoing MTT analysis each day for days 2-5. Paclitaxel loadedmicroparticles and DMSO microparticles were added to serum rich mediaand individually assessed on tumor cells of the same plate. The resultsdemonstrate a dose-dependent inhibition with the administration ofpaclitaxel microparticles, but little difference in inhibition for agiven dose on day 2 vs. day 5. These findings confirm that paclitaxelmicroparticles inhibit tumor growth quickly with little difference ingrowth inhibition following the initial exposure. This is consistentwith an immediate release of drug and maximum burst effect.

Example 38 Nanoparticle Uptake by Cells

Fluorescent nanoparticles were created as describe herein with theaddition of 2 mol % of a fluorescent co-monomer. Non-small cell lungcancer A549 cells were seeded onto a 96-well plate (20,000 cells/well)and incubated overnight at 37° C. and 5% carbon dioxide. The media wasthen removed from the wells and replaced with a buffered saline solutioncontaining fluorescent nanoparticles at a concentration of 0.5, 1, or 5mg/mL. Controls not containing nanoparticles were also performed. Afterincubation at 37° C. and 5% carbon dioxide for 0.5, 1, 2, or 4 hours,the particle suspension was removed, and the cells were washed twicewith buffered saline and then lysed with 100 μL of 0.5% Triton X-100® in0.2 M sodium hydroxide. Measuring the fluorescence of the cell lysatesamples (excitation wavelength=470 nm, emission wavelength=518 nm) andcomparing to a standard curve gave the concentration of nanoparticles inthe samples. The cells showed increasing uptake over time and withdecreased nanoparticle concentration in the buffer.

Example 39 Cell Culture

Mesothelioma cell line (MSTO-211H) is incubated (37° C., 5% CO₂) withMEM (with 10% fetal bovine serum (FBS), 1% essential amino acids, and 1%Penicillin/Streptomyocin with L glutamine (Pen/Strep), F-12 HAM (with10% FBS and 1% Pen/Strep) and DMEM (with 10% FBS and 1% Pen/Strep) mediarespectively, with media changes once every three days. When notcultured, all cell lines were stored in RPMI freezing media at −80° C.(with 50% FBS, 40% RPMI and 10% dimethyl sulfoxide (DMSO)). Cell lineswere trypsinized from 15 cm plates and seeded into 96 well plates at aconcentration of 3000 cells per well. All cell lines were cultured for aperiod of at least three days before being tested in cell proliferationassays.

Example 40 Pemetrexed In Vitro Mesothelioma Tumor Cell ProliferationAssays

Cells were washed with sterile phosphate buffered saline (PBS) andtrypsinized. The cells were then counted using a Coulter counter andplated 3,000 cells/well in 96 well plates. Cells were serum starvedovernight and then treated with pemetrexed, control poly(hydroxyglycerol carbonate-co-ε-caprolactone) microparticles or pemetrexedloaded poly(hydroxy glycerol carbonate-co-ε-caprolactone) microparticlesthe next day. A positive control contained 10% FBS or the sameconcentration of FBS provided for treated cells, while a negativecontrol lacked FBS. At the completion of the assay the cells wereincubated with 50 μl of 1× Thiazolyl Blue Tetrazolium Bromide (MTT,Sigma) dissolved in PBS at 37° C. for two hours. The media was thenaspirated and 100 μl of DMSO was added to each well. The plates werethen placed on a shaking device for 10 minutes and the wells turnedpurple, corresponding to the number of viable mitochondria in the well.The plates were placed on an ELISA reader and scanned at a wavelength of570 nm. The absorbance values were normalized to values from a knownnumber of stained cells. The dose of pemetrexed at which 50% of cellswere killed, or LD50, was determined to be between 0.1-1.0 μg/mL.Approximately 250,000-500,000 pemetrexed loaded microparticles/well or100 microparticles/tumor cell were necessary to achieve similarpemetrexed concentrations and cell death.

Example 41 Release of 10-Hydroxycamptothecin from Films for In VitroTumor Cell Proliferation Assays

Polymer films containing 10-hydroxycamptothecin (10-HCPT) were cast ontoglass by depositing a polymer solution comprised of poly(stearic acidcarbonate-co-ε-caprolactone) (5 mg), dichloromethane (50 μL) and10-hydroxycamptothecin (100 μg) using a microsyringe. Films were exposedto Ultraviolet (UV) radiation overnight prior to being placed into12-well plates containing 3,000 Lewis Lung Carcinoma (LLC) cells perwell. Cell cultures were incubated with films for multiday exposure(FIG. 1) or 24-hour (FIG. 2) periods and then assayed for viabilityusing MTT staining protocols. Both exposure durations provided effectiveinhibition of tumor cell proliferation out to 25 days and themultidayexposure period continued to effectively kill tumor cells aslate as Day 30. By comparison, exposure to films containing no drug(unloaded films) under the same exposure conditions generated nocytotoxic effects (see FIGS. 1 and 2). These results indicate that ourpolymer films containing 10-hydroxycamptothecin (10-HCPT) caneffectively kill tumor cells for as long as thrity days.

Example 42 In Vitro Tumor Cytoxicity with Paclitaxel-loadedNanoparticles

Cultured tumor cell lines for lung (murine LLC and human A549 andNCI-H460), melanoma (B16), mesothelioma (human MSTO-211H), breast (humanMCF7), human esophageal sarcoma (LMS05) cancers were cultured at 37°C./5% CO₂ in the appropriate media supplemented with 10% Fetal BovineSerum (FBS) and 1% penicillin/streptomycin with L-glutamine, with theexception of MEM media which also contained 1% essential amino acids and1 mg/mL of bovine insulin. Each cell line was seeded at concentrationsof 3,000 (LLC, B16, A549, MSTO-211H, NCI-H460), 5,000 (MCF7) or 10,000(LMSO5) cells/well into 96-well assay plates in order to establish theappropriate tumor cell plating density. Cells were co-cultured for 7days with paclitaxel-loaded and unloaded5-methyl-2-(2,4,6-trimethoxyphenyl)-1,3-dioxan-5-yl-methyl methacrylatenanoparticles (fabrication described above). After the incubationperiod, cells were assayed for viability via MTT analysis and plotted asthe percentage of viable cells using a positive control (culturecontaining no nanoparticles) to represent 100% viability.

FIG. 16 shows the results for LLC and FIG. 17 shows the results forMSTO-211H experiments and indicate that paclitaxel-loaded, but notunloaded, nanoparticles reduce cell proliferation for several differentcancer lines at a concentrations as low as 10 μg/mL of polymernanoparticles (containing approximately 100 ng/mL of Paclitaxel,consistent with the IC₅₀ of free paclitaxel). FIG. 18 shows theanti-cancer activity of paclitaxel loaded nanoparticle with LLC cells invitro. These results indicate that our polymers have sustained release,and that when loaded with an anti-cancer agent can actively kill cancercells for sustained periods of time, which we believe may inhibitrecurrence of the cancer.

Example 43 Quantification of Microparticle Adherence to Lung

To investigate microparticle attachment to lung tissue, PLGAmicroparticles were suspended in Pluronic NF-127 or water and eachsolution was painted onto the intact mouse lungs. The lungs were rockedside-to-side in PBS, simulating the coating of pleural fluid, fordiffering time periods and the percent of adherent microparticles wasdetermined using a coulter counter. After a one hour exposure to PBSwetting the lung, the supernatant was removed and counted for adherentmicroparticles. Plates were thoroughly rinsed to avoid counting adhesionto the plate rather then lung. The percent of microparticles adhering tolung was found by averaging the number of microparticles released to thesupernatant. It was found that there is a much higher percent attachment(89.9+/−10) of microparticles loaded in Pluronic NF127 gel than withmicroparticles loaded in a water control (28.3+/−28). The difference inthese attachment percentages is statistically significant (P<0.05), andindicates that adhesives such as PLURONIC® NF127 gel can be used toadhere micropartilces to tissue, such as lung tissue.

Example 44 Anti-Tumor Response In Vivo

Lewis Lung Carcinoma cells (LLC) (750,000) were injected with or without50 million PLGA-Paclitaxel loaded microparticles subcutaneously inC57BL6 mice. It is well established that this tumor dose results insubcutaneous tumor nodules within 1 week with rapid growth requiringsacrifice within 2-3 weeks. In the time following injection it was foundthat tumor size was significantly decreased in animals receiving LLCcells and PLGA-paclitaxel microparticles vs. LLC cells alone. Atsacrifice, untreated tumors weighed 3.8±0.9 grams whereas tumorsco-injected with PLGA-paclitaxel loaded microparticles (n=7) weighed1.0±1.4 grams (Day 13-17, p<0.05). The majority of PLGA-paclitaxelloaded microparticle treated animals developed minimal evidence of tumorimplantation or growth. No toxicity from PLGA-paclitaxel administrationwas noted. Thus, the data suggests that locally delivered chemotherapyvia microparticles can deter the growth and establishment of lungcarcinoma in vivo in this subcutaneous model of tumor implantation.

Fabricated microparticles were 1-5 μm in diameter, smooth, and lackporosity suggesting that they will maintain a relatively constant drugrelease for a long period of time. It is estimated that paclitaxel hastumorcidal effects in the 5-10 ng range, which is estimated to be about3 microparticles per cell. In vivo co-injection of tumor cells andPaclitaxel loaded microparticles demonstrate that a dose of 100 millionmicroparticles completely inhibits growth and establishment of tumorcells. Proliferation assays and in vivo injections have alsodemonstrated that the control PLGA microparticles are inert and withouteffect on tumor growth.

Example 45 Anti-Tumor Response of Functional Loaded Nanoparticles InVivo

The anti-tumor effects of chemotherapy-loaded nanoparticles from Example18 were evaluated in well-established subcutaneous tumor models. MouseLLC or human MSTO-211H cancer cell lines were implanted into C57BL6 ornude mice, respectively. Cultured tumor cell suspensions wereco-injected with drug-loaded nanoparticles into the subcutaneous tissuesof the back of mice. Both “high” (25 microgram paclitaxel) and “low”(2.5 microgram paclitaxel) doses of nanoparticles were evaluated.Animals injected with tumor cells alone in PBS, tumor with identicaldoses of unloaded functional or loaded non-functional (non-expansile)nanoparticles served as controls. Tumor size was monitored biweekly andanimals were euthanized if tumors reached 2 cm in size. As demonstratedFIG. 13, both the high and low doses of paclitaxel-loaded functionalnanoparticles inhibited tumor growth in mice (p<<0.0001), and were muchmore effective than even the paclitaxel-loaded but non-expansilenanoparticles. These data clearly demonstrate that the anti-tumoreffects of paclitaxel-loaded functional nanoparticles seen in vitrotranslates to suppression of tumor growth in vivo.

Example 46 Anti-Tumor Response of Subcutaneous Polymer Film ImplantationIn Vivo

The anti-tumor effects of chemotherapy-loaded polymer film implants werealso evaluated using a subcutaneous tumor model. After induction ofanesthesia, C57BL/6 mice were shaved and skin on the back of the mousewas prepped in a sterile fashion. An incision of 0.8 cm was made betweenthe shoulders of the mice. The connective tissue under the skin wasdissected with a pair of sterilized tweezers to make a subcutaneouspocket. A piece of sterilized polymer film dried on a pericardium strip(0.8×0.8 cm) was inserted into the subcutaneous pocket with thedrug-loaded side of the film placed upward towards the skin, and theincision was closed with 5-0 sutures. Mice were monitored until fullyrecovered from anesthesia, given analgesics and were housed in a SPF(specific pathogen free) grade animal facility. Two days were allowedfor healing of the incision, before 750,000 mouse LLC tumor cells wereinjected subcutaneously on top of the implanted film via a 27-guageneedle.

Tumor size was monitored biweekly and animals were euthanized if tumorsreached 2 cm in size. Tumor growth did not occur overtop of polymerfilms loaded with 30 μg 10-hydroxycamptothecin (10-HCPT) in any of theexperimental mice (see FIG. 14). This is in contrast to the significanttumor growth that occurred directly on the unloaded polymer films inover 75% of the animals tested. Some animals that had received 10-HCPTloaded polymer films did develop tumors with delayed follow-up but thesetumors were always in the periphery of the pocket and away from the filmitself (see FIG. 15). In addition to the delay in tumor appearance,these tumors were significantly smaller in size (p<0.005), confirmingthat the 10-HCPT loaded films prevented and/or delayed local tumorgrowth in the in vivo tumor model.

Example 47 No Delay In Wound Healing In the Presence of SubcutaneousChemotherapy-Loaded Polymer Films

Polymer films were subcutaneously implanted on the back of C57BL/6 miceunder anesthesia as described herein. Healing was assessed by inspectionin animals that received 10-HCPT loaded polymer films, unloaded polymerfilms or sham surgery where subcutaneous pockets were prepared but nofilm was implanted. All incisions were closed with 5-0 suture. There wasno evidence of wound dehiscence early or late (up to 21 days) in animalsthat received loaded or unloaded films. In addition, there was nodifference in erythema or wound appearance among animals with filmsversus sham surgery.

Example 48 Local Drug Release of Subcutaneous Polymer Film ImplantationIn Vivo

The local drug release pattern of subcutaneously implanted drug-loadedpolymer films in vivo was examined. Polymer films were subcutaneouslyimplanted on the back of C57BL/6 mice under anesthesia as describedabove. At weekly intervals following implantation of the films, thesurrounding tissues were harvested. These tissues were cut in a radialfashion away from the film and sequentially segmented at 1 mm distancesaway from the film, thus providing tissue for assessment at variousdistances and directions away from the drug-loaded film. Theconcentration of the drug eluted at the various distances was thenascertained within each tissue segment using HPLC for the specific drugof interest. The gradient of drug concentration within a 2 cm diameterof the center of the film was then plotted to establish the drug releasekinetics and drug distribution into the surrounding tissues in vivo.

Example 49 Tumor Recurrence Model of Subcutaneous Tumor Resection

The suppression of tumor recurrence by drug-loaded nanoparticles anddrug-loaded polymer films are also being examined using a wellestablished in vivo tumor model (Qadri et al., Ann Thorac Surg80:1046-51, 2005). Similar to the subcutaneous tumor model utilized inExample 48, 750,000 LLC tumor cells were injected subcutaneously andallowed to grow. The tumor was subsequently resected through a 1.0 cmincision parallel to the tumor and the entire tumor is removed and theincision closed in control animals. Unloaded or drug-loadednanoparticles or polymer films are applied onto the tumor bed ofexperimental animals and the skin incision is similarly closed. Animalsare assessed biweekly for evidence of recurrent tumor growth which ourpilot studies have demonstrated occurs aggressively in control animalsthat do not receive drug-loaded nanoparticles or polymer films.

Example 50 In Vivo Intraperitoneal Mesothelioma Animal Experiment withPaclitaxel-Loaded Nanoparticles

The ability of drug-loaded nanoparticles to inhibit the growth of humantumor cells in vivo within the intraperitoneal cavity has also beeninvestigated using a murine model of mesothelioma using a wellestablished in vivo tumor model (Adusumilli et al., J Thorac CardiovascSurg. 132:1179-88, 2006). Cultured mesothelioma tumor cells (5 millionMSTO-211H) were co-injected with paclitaxel-loaded functionalnanoparticles via an i.p. injection into the lower abdomen of NU/J(nude) mice. Animals injected with tumor cells alone in PBS or tumorwith identical doses of loaded non-functional (non-expansile)nanoparticles served as controls for tumorigenicity and nanoparticletoxicity, respectively.

Example 51 SEM of Films

Drug-loaded polymer films were cast onto glass by depositing a polymersolution comprised of poly(stearic carbonate-co-ε-caprolactone) (5 mg),dichloromethane (50 μL), and 10-hydroxycamptothecin (100 μg), using amicrosyringe. The solvent was removed by slow evaporation over night andthen placed under reduced pressure for 24 hours. Prior to imaging, thefilms were coated with 7 nm of Au/Pd. The films were imaged usingscanning electron microscopy. The surfaces of the films appeared smoothand non-porous with fibrous-like microtexture. As shown in FIG. 8,cross-section images also revealed a smooth, non-porous interior withconsistent thicknesses throughout the length of the film ofapproximately 40 microns.

Example 52 SEM of Nanoparticles

Samples for scanning electron microscope (SEM) imaging were prepared bydiluting a sample of nanoparticles to a concentration of 0.25 mg/mL withdeionized water. A 10 μL portion of the diluted sample was then placedon a clean aluminum stub and allowed to air dry. Prior to imaging, thesamples were coated with a 5 nm layer of Au/Pt. Samples were then imagedon a Zeiss SUPRA 40VP field emission SEM using an accelerating voltageof 1 kV. The image in FIG. 11 shows particles from about 1 to 50 micronswith most of the particles between 5 and 20 microns.

Example 53 Contact Angle Measurements

Polymer films were cast onto glass substrates and the contact angle ofeach film was determined using contact angle goniometry. Contact anglesranged from 75-120°. For example, the contact angle of poly(stearic acidcarbonate-co-ε-caprolactone) was 118°. The contact angle of glass isabout 35°.

Example 54 Thermal Transition Measurements

Thermal transitions of each polymer were measured using differentialscanning calorimetry. Polymers composed of ε-caprolactone and benzyloxyglycerol carbonate monomers were formed with the following carbonatemole fractions: 0.05, 0.10, 0.20, 0.30, 0.40, 0.50, 1.00. Glasstransition temperatures ranged from −64° C. to −10° C. and meltingtemperatures ranged from 22° C.-57° C. Some copolymers weresemi-crystalline and other copolymers were amorphous.

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1. An oligomer or polymer having a repeat unit represented by FormulaXX:

wherein: Q is selected from among O, S, Se, or NH; G is selected fromamong the following structures:

R₂ is selected from among hydrogen, a straight or branched alkyl,cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl,arylalkyl, or fluorocarbon chain of 1-50 carbons, wherein each alkyl,cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl,arylalkyl, or fluorocarbon chain is optionally substituted internally orterminally by one or more hydroxyl, hydroxyether, carboxyl,carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol,thioester, sulfate, phosphate, phosphonate, or halogen substituents; R₃is selected from among hydrogen, methoxy, ethoxy, amino, a straight orbranched alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl,alkylaryl, or arylalkyl chain of 1-10 carbons; R₄, R₅, and R₆ are eachindependently selected from among a straight or branched alkyl,cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, orarylalkyl chain of 1-10 carbons; and R₇ and R₈ are each independentlyselected from among hydrogen, a straight or branched alkyl, cycloalkyl,aryl, olefin, alkylaryl, or arylalkyl chain of 1-50 carbons, whereineach alkyl, cycloalkyl, aryl, olefin, alkylaryl, or arylalkyl chain isoptionally substituted internally or terminally by one or more hydroxyl,hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- ordi-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate,or halogen substituents.
 2. The oligomer or polymer of claim 1, whereinthe oligomer or polymer is represented by Formula XX′:

wherein: n is an integer from 2-750, and wherein each oligomeric orpolymeric chain has a terminal group, the terminal group being selectedfrom among amines, thiols, amides, phosphates, sulphates, hydroxides,alkenes, and alkynes.
 3. The oligomer or polymer of claim 1, wherein R₂is hydrogen or methyl.
 4. The oligomer or polymer of claim 1, wherein Qis oxygen.
 5. A composition comprising the oligomer or polymer ofclaim
 1. 6. A polymeric film or particle comprising an oligomer orpolymer of claim
 1. 7. A polymeric particle of claim 6, comprising amicroparticle or nanoparticle.
 8. A polymeric particle of claim 7,wherein the particle has a diameter between about 2 nm and 1 micron. 9.The polymeric particle of claim 7 comprising a first volume at a firstpH, and a second volume at a second pH, different from the from thefirst pH.
 10. The polymeric particle of claim 9, wherein the secondvolume is 1× or more greater than the first volume when the second pH islower than the first pH.
 11. The polymeric particle of claim 9, whereinthe second volume is 4× or more greater than the first volume when thesecond pH is lower than the first pH.
 12. The polymeric particle ofclaim 9, wherein the second volume is 8× or more greater than the firstvolume when the second pH is lower than the first pH.
 13. The polymericparticle of claim 9, wherein the second volume is greater than the firstvolume and the change in volume is sufficient that the particle whenwithin a cell during the volume change ruptures the cell or a cellularcompartment.
 14. The polymeric particle of claim 9, wherein the secondvolume is greater than the first volume and the change in volume issufficient to cause the particle to become lodged, embedded, orimmobilized in an anatomic location, such as a lymph node, airway,cavity, capillary, or other tissue.
 15. The polymeric film or particleof claim 6, further comprising an agent.
 16. The polymeric film orparticle of claim 15, wherein the agent is a biologically active agentcomprising one or more of an anti-cancer agent, an anti-biotic, ananti-neoplastic agent, an analgesic, an angiogenic, or an agent thatpromotes wound healing.
 17. The polymeric film or particle of claim 15,wherein the biologically active agent comprises one or more ofasparaginase; bleomycin; busulfan; capecitabine; carboplatin; carmustinechlorambucil; cisplatin; cyclophosphamide; cytarabine; dacarbazine;dactinomycin; daunorubicin; dexrazoxane; docetaxel; doxorubicin;etoposide; floxuridine; fludarabine; fluorouracil; gemcitabine;hydroxyurea; idarubicin; ifosfamide; irinotecan; lomustine;mechlorethamine; melphalan; mercaptopurine; methotrexate; mitomycin;mitotane; mitoxantrone; paclitaxel; pemetrexed; pentostatin; plicamycin;procarbazine; rituximab; streptozocin; teniposide; thioguanine;thiotepa; vinblastine; vincristine; and vinorelbine.
 18. A method ofusing the particle or film of claim 6, the method comprising applying toone or more of the following: (i) a surgical resection margin, (ii)within a treated or untreated tumor or cavity, (iii) a target site ofdisease away from a surgical margin, and (iv) a lymph node.
 19. The filmof claim 6, wherein the film is a single layered film.
 20. The film ofclaim 15, further comprising two or more layers to form a multi-layeredfilm.
 21. The film of claim 15, comprising a first layer comprising afirst polymer of Formula XX, and a second layer comprising a secondpolymer different from Formula XX.
 22. The film of claim 21, wherein thesecond polymer comprises one or more of poly(lactic acid), poly(glycolicacid), poly(lactic-co-glycolic acid), polycaprolactone,poly(trimethylene carbonate), polyester, polycarbonate, and polyamide.23. An oligomer or polymer, or portion thereof, represented by FormulaXXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI,XXXII, XXXIII, XXXIV, XXXV, XXXVI or XXXVII:

wherein: Q′ is independently selected from among O, S, Se, or NH; G′,G₁′, and G₂′ are each independently selected from among the followingstructures:

or R₁′; wherein G₁′ and G₂′ are not the same; R₁′ is selected from amonga straight or branched alkyl, cycloalkyl, aryl, olefin, silyl,alkylsilyl, arylsilyl, alkylaryl, arylalkyl, or fluorocarbon chain of3-50 carbons, wherein each alkyl, cycloalkyl, aryl, olefin, silyl,alkylsilyl, arylsilyl, alkylaryl, arylalkyl or fluorocarbon chain isoptionally substituted internally or terminally by one or more hydroxyl,hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- ordi-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate,or halogen substituents; or R₁′ is selected from among poly(ethyleneglycol), poly(ethylene oxide), poly(hydroxyacid)), a carbohydrate, aprotein, a polypeptide, an amino acid, a nucleic acid, a nucleotide, apolynucleotide, any DNA or RNA segment, a lipid, a polysaccharide, anantibody, a pharmaceutical agent, or any epitope for a biologicalreceptor; or R₁′ is selected from among a photocrosslinkable orionically crosslinkable group; R₂′ is selected from among hydrogen, astraight or branched alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl,arylsilyl, alkylaryl, arylalkyl, or fluorocarbon chain of 1-50 carbons,wherein each alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl,arylsilyl, alkylaryl, arylalkyl, or fluorocarbon chain is optionallysubstituted internally or terminally by one or more hydroxyl,hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- ordi-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate,or halogen substituents; x and y are each independently selected from aninteger of 2-750; a is selected from an integer of 1-25; b is selectedfrom an integer of 1-14; c is selected from an integer of 1-14; and eachpolymeric terminal group is selected from among amines, thiols, amides,phosphates, sulphates, hydroxides, metals, alkanes, alkenes and alkynes.24. An oligomer or polymer, or portion thereof, represented by FormulaXXXVIII:

wherein: Q′ is independently selected from among O, S, Se, or NH; G′ isselected from among

or R₁′; R₁′ is selected from among a straight or branched alkyl,cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl,arylalkyl, or fluorocarbon chain of 3-50 carbons, wherein each alkyl,cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl,arylalkyl, or fluorocarbon chain is optionally substituted internally orterminally by one or more hydroxyl, hydroxyether, carboxyl,carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol,thioester, sulfate, phosphate, phosphonate, or halogen substituents; orR₁′ is selected from among poly(ethylene glycol), poly(ethylene oxide),poly(hydroxyacid)), a carbohydrate, a protein, a polypeptide, an aminoacid, a nucleic acid, a nucleotide, a polynucleotide, any DNA or RNAsegment, a lipid, a polysaccharide, an antibody, a pharmaceutical agent,or any epitope for a biological receptor; or R₁′ is selected from amonga photocrosslinkable or ionically crosslinkable group; x and y are eachindependently selected from an integer of 2-750; e is selected from aninteger of 1-8; and each polymeric terminal group is selected from amongamines, thiols, amides, phosphates, sulphates, hydroxides, metals,alkanes, alkenes and alkynes.
 25. The oligomer or polymer of claim 24,wherein R₁′ is selected from among a straight or branched alkyl,cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl,arylalkyl, or fluorocarbon chain of 3-50 carbons, wherein each alkyl,cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl,arylalkyl, or fluorocarbon chain is optionally substituted internally orterminally by one or more hydroxyl, hydroxyether, carboxyl,carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol,thioester, sulfate, phosphate, phosphonate, or halogen substituents. 26.The oligomer or polymer of claim 24, wherein R₁′ is selected from amonga straight or branched alkyl, cycloalkyl, aryl, olefin, silyl,alkylsilyl, arylsilyl, alkylaryl, arylalkyl, or fluorocarbon chain of3-50 carbons.
 27. The oligomer or polymer of claim 24, wherein R₁′ isselected from among a straight or branched alkyl chain of 3-50 carbons.28. A polymeric film or particle comprising a polymer of claim 23 or 24.29. A polymeric particle of claim 28, comprising a microparticle ornanoparticle.
 30. A polymeric particle of claim 29, wherein the particlecomprises a diameter of between about 1 nm and 2 microns.
 31. Apolymeric particle of claim 29, wherein the particle comprises adiameter between about 10 nm and 1 microns.
 32. The polymeric film orparticle or claim 28, further comprising an agent.
 33. The polymericfilm or particle of claim 32, wherein the agent is a biologically activeagent comprising one or more of an anti-cancer, an anti-biotic,anti-neoplastic, an analgesic, an angiogenic, or agent that promoteshealing.
 34. The polymeric film or particle of claim 32, wherein thebiologically active agent comprises one or more of asparaginase;bleomycin; busulfan; capecitabine; carboplatin; carmustine chlorambucil;cisplatin; cyclophosphamide; cytarabine; dacarbazine; dactinomycin;daunorubicin; dexrazoxane; docetaxel; doxorubicin; etoposide;floxuridine; fludarabine; fluorouracil; gemcitabine; hydroxyurea;idarubicin; ifosfamide; irinotecan; lomustine; mechlorethamine;melphalan; mercaptopurine; methotrexate; mitomycin; mitotane;mitoxantrone; paclitaxel; premetrexed; pentostatin; plicamycin;procarbazine; rituximab; streptozocin; teniposide; thioguanine;thiotepa; vinblastine; vincristine; and vinorelbine.
 35. A method ofusing the particle or film of claim 32, the method comprising applyingto one or more of the following: (i) a surgical resection margin, (ii)within a treated or untreated tumor or cavity, (iii) a target site ofdisease away from a surgical margin, and (iv) a lymph node.
 35. The filmof claim 32, wherein the film is a single layered film.
 36. The film ofclaim 32, further comprising two or more layers to form a multi-layeredfilm.
 37. The film of claim 32, comprising a first layer comprising afirst polymer of Formula XX, and a second layer comprising a secondpolymer different from Formula XX.
 38. The film of claim 33, wherein thesecond polymer comprises one or more of poly(lactic acid), poly(glycolicacid), poly(lactic-co-glycolic acid), polycaprolactone,poly(trimethylene carbonate), polyester, polycarbonate, and polyamide.39. An oligomer or polymer having a repeat unit represented by FormulaXX:

wherein: G comprises a first group that is convertible to a second groupdifferent from the first group at a pH at or below about 6.0; R₂ isselected from among hydrogen, a straight or branched alkyl, cycloalkyl,aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl, orfluorocarbon chain of 1-50 carbons, wherein each alkyl, cycloalkyl,aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl orfluorocarbon chain is optionally substituted internally or terminally byone or more hydroxyl, hydroxyether, carboxyl, carboxyester,carboxyamide, amino, mono- or di-substituted amino, thiol, thioester,sulfate, phosphate, phosphonate, or halogen substituents; and Q isselected from among O, S, Se, or NH.
 40. The oligomer or polymer ofclaim 39, wherein G is selected from among the following structures:


41. A particle having a first volume and comprising an oligomer orpolymer having a repeat unit represented by Formula XX:

wherein: G comprises a first group that is convertible to a second groupdifferent from the first group at a pH at or below about 6.0; R₂ isselected from among hydrogen, a straight or branched alkyl, cycloalkyl,aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl, orfluorocarbon chain of 1-50 carbons, wherein each alkyl, cycloalkyl,aryl, olefin, silyl, alkylsilyl, arylsilyl, alkylaryl, arylalkyl, orfluorocarbon chain is optionally substituted internally or terminally byone or more hydroxyl, hydroxyether, carboxyl, carboxyester,carboxyamide, amino, mono- or di-substituted amino, thiol, thioester,sulfate, phosphate, phosphonate, or halogen substituents; and Q isselected from among O, S, Se, or NH; and wherein when the particle isplaced in an environment having a pH at or below about 6.0, the particleincreases in volume from the first volume to a second volume that ismore than two times the first volume after equilibrium is established.